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Palombini, Giancarlo. "Dall’etnomusicologia all’acustemologia." Anuac 7, no. 1 (July 24, 2018): 217–23. http://dx.doi.org/10.7340/anuac2239-625x-3384.
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Nota critica di Nicola Scaldaferri, ed, Santi, animali e suoni: Feste dei campanacci a Tricarico e San Mauro Forte, 1 CD allegato, Udine, Nota, Geos cd book, Musica e cultura tradizionale della Basilicata, 4, 2005, pp. 96; Nicola Scaldaferri, Steven Feld, eds, I suoni dell’albero: Il Maggio di S. Giuliano ad Accettura, 2 CD allegati, Udine, Nota, Geos cd book, Musica e cultura tradizionale della Basilicata, 6, 2012, pp. 132.
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Giuffrida, Dario, Viviana Mollica Nardo, Daniela Neri, Giovanni Cucinotta, Irene Vittoria Calabrò, Loredana Pace, and Rosina Celeste Ponterio. "A Multi-Analytical Study for the Enhancement and Accessibility of Archaeological Heritage: The Churches of San Nicola and San Basilio in Motta Sant’Agata (RC, Italy)." Remote Sensing 13, no. 18 (September 17, 2021): 3738. http://dx.doi.org/10.3390/rs13183738.
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In the coming years, Italy will need to take on a great challenge concerning the digitization of its archaeological and architectural heritage, one of the richest and most problematic in the world. The aim is to improve the knowledge, conservation, enhancement and accessibility of cultural assets and to make them a resource for national and local development. In this process, the next generation of 3D survey methods (laser scanning and photogrammetry), in combination with diagnostic techniques (spectroscopy analyses) and GIS/BIM (Geographic Information System/Building Information Modeling) solutions, represent a valid support. This work, part of a broader intervention launched by the Municipality of Reggio Calabria for the requalification of some archaeological sites located within its urban and metropolitan area, is focused on the study case of Motta S. Agata. The ancient settlement is located 8 km from Reggio C. in a hilly area difficult to reach and preserves numerous structures in a state of ruin. Among these, two interesting medieval churches are proposed for examination: the church of San Nicola, characterized by five hypogeal funeral crypts, and the chapel of San Basilio, which preserves the traces of a wall painting. A multi-methodological approach including close-range photogrammetry, laser scanning and chemical and thermal analyses was adopted in order to fulfill different tasks: creating a topographic model of the hillfort, mapping the archaeological evidence, digitizing and returning 3D models of the churches, characterizing materials through chemical analyses and monitoring the surfaces with thermal imaging. These combined applications have contributed to reaching the planned goals, i.e., study, conservation, diagnostics, preparation for restoration interventions, development of digital media and dissemination. In this way, a type of interactive museum (made up of virtual tours and informative digital models) has been made available in order to improve the site’s accessibility and inclusivity as well as to test the effect of digitization in attracting tourists and local people toward a place located outside of the usual tourist circuits.
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Mariano, F., M. Saracco, and L. Petetta. "THE SEAPLANE BASE IVO MONTI AT S. NICOLA VARANO (FG): A MONUMENT OF MILITARY ARCHEOLOGY, BETWEEN HISTORY AND PROTECTION." ISPRS - International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences XLII-5/W1 (May 16, 2017): 419–25. http://dx.doi.org/10.5194/isprs-archives-xlii-5-w1-419-2017.
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Built in the years between 1915 and 1918, and located on the west bank of the “Varano” Lake, a bay running along the village of “Cagnano Varano”, the “Ivo Monti” seaplane base was erected on a pre-existing medieval settlement which belonged to the Benedictine Monks from the town of “San Nicola Imbuti”. <br><br> During WWI, this seaplane base was turned, from a simple water airport, into a strategic military base for floatplanes. As a matter of fact, the large lagoon could be used as landing spot for the planes sent off to patrol the dalmatic coast, one of the historical regions of Croatia, then controlled by the Austrians. <br><br> After WWI, after the seaplane became an outdated technology, the “Ivo Monti” base was progressively dismantled and then totally abandoned at the beginning of the 1950s. <br><br> In 2014, considering the historical relevance of this site and the unmistakable architectural value of its elements, a research framework agreement was signed between the “DICEA” Department of Marche Polytechnic University and the city council of the town hosting the site, aimed at the development of shared scientific research projects revolving around the study, the valorisation, and the restoration of the military complex in question, which had been in a complete state of decay and neglect for too long. <br><br> The still ongoing research project mentioned presents two main missions: the first is the historical reconstruction, the geometric mapping, and the robustness analysis of the ruins, by studying and faithfully representing the state of deterioration of the building materials and of the facilities; the second is the identification and the testing of potential architectural solutions for the conversion and the reuse of the site and of its facilities.
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Wade, Mark, Emiliano Tamanini, Mathieu Unbekandt, Nicola Wallis, John Lyons, Joanne Munck, Andrew Woodhead, et al. "Abstract 5902: Targeting MAPK-driven tumors via inhibition of MAP2K4." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5902. http://dx.doi.org/10.1158/1538-7445.am2024-5902.
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Abstract MAPK pathway activation is a feature of multiple tumor types. Drugging KRAS and BRAF, the two main oncogenic drivers in the MAPK pathway, has proven successful in the clinic. Inhibition of the downstream effectors, MEK and ERK, can also induce tumor regression. Despite this, many tumors are intrinsically resistant to MAPK pathway inhibitors, or acquire resistance under selective pressure to drug treatment. This creates a need for combination treatments to improve clinical responses. A synthetic lethal (SL) interaction between inhibition of the MAPK pathway and blockade of JNK-JUN signaling has recently been described1. Specifically, data from yeast genetics and CRISPR knockout experiments in human cells have identified MAP2K4 as a potential therapeutic target that could be combined with MAPK inhibitors. To date, however, no potent MAP2K4 inhibitors with in vitro and cellular selectivity against key anti-targets have been reported. Here, we describe the development of potent covalent inhibitors of MAP2K4 kinase activity. Biochemical and cell-based assays show that the compound(s) are selective for MAP2K4 versus anti-targets including MAP2K7 and ERK kinases. The combination of MAP2K4 and MEK/ERK inhibitors was effective in cell lines driven by MAPK signaling. These data provide the rationale for further development of MAP2K4 inhibitors to advance our understanding of this novel drug combination. References: 1. Xue Z, Vis DJ, Bruna A, Sustic T, van Wageningen S, Batra AS, et al. MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell Res. 2018; 28:719-29. Citation Format: Mark Wade, Emiliano Tamanini, Mathieu Unbekandt, Nicola Wallis, John Lyons, Joanne Munck, Andrew Woodhead, Patrick Schopf, Jessie Stow, Charlotte East, Mellissa Clark, Jeffrey St. Denis, Puja Pathuri. Targeting MAPK-driven tumors via inhibition of MAP2K4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5902.
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Willmore, Elaine, Maria Ahn, Suzanne Kyle, Yan Zhao, Huw Thomas, Kenneth S. Rankin, Luke Bevan, et al. "Abstract 3333: Targeting the MDM2-p53 interaction: Time- and concentration-dependent studies in tumor and normal human bone marrow cells reveal strategies for an enhanced therapeutic index." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3333. http://dx.doi.org/10.1158/1538-7445.am2024-3333.
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Abstract Aim We aimed to design an MDM2-p53 antagonist with a differentiated tolerability profile that could be used to treat patients with wild-type TP53 malignancies. As part of an alliance between Newcastle University, Astex Pharmaceuticals, and Cancer Research Horizons, we discovered ASTX295, a potent inhibitor of the MDM2-p53 interaction that is currently under clinical investigation in patients with solid tumors (NCT03975387). We selected ASTX295 as a compound with a predicted short plasma half-life, which we hypothesised would help to mitigate the dose-limiting neutropenia and thrombocytopenia observed with earlier MDM2-p53 antagonists in clinical studies. To examine this hypothesis in vitro, we determined time- and concentration-dependent responses to ASTX295 treatment in healthy volunteer-derived human bone marrow cells, megakaryocytes, and in a panel of human tumor cell lines. Methods Samples containing bone marrow cells from healthy patients undergoing hip surgery were obtained under the ethical approval of the Newcastle Biobank (REC 12/NE/0395). Following Lymphoprep™ separation, cells were treated ex vivo with ASTX295 and seeded for Granulocyte-macrophage (GM) colony-forming assays in methylcellulose. Megakaryocytes were obtained from in vitro differentiation of CD34+ stem/progenitor cells. Human tumor cell lines (including MDM2-amplified SJSA-1) were treated with ASTX295 in vitro and seeded at low density for colony-forming assays. Exposures of 6, 12, or 24h were examined, and the data plotted to calculate LC50 values. Results The clonogenic survival of tumor cells was time-dependent, with LC50 values (mean ± SEM) in SJSA1 cells being 238 ± 46nM and 75 ± 7nM respectively (n = 3-4), following a 12h or 24h exposure to ASTX295. Time-dependent effects were also evident in five human bone marrow samples but with LC50 values of 1.9, >3, >10, >10, and >10uM being achieved at 12h, and 860 ± 268nM at 24h. Megakaryocytes showed similar time-dependent sensitivities in which daily treatment of 2 or 6h over three days did not induce apoptosis while significant cell death was observed when the treatment time was extended to 16-24h daily. In contrast, short, daily pulse treatment of 2-6h in cell lines (MV4-11, MOLM-13, SJSA-1) over three days was sufficient to induce cell death. Conclusions ASTX295 is a potent antagonist of the MDM2-p53 interaction. Collectively, our in vitro data suggest that a shorter exposure to ASTX295 (up to 12h), may help to spare healthy bone marrow cells whilst killing tumor cells. Hence, intermittent exposure to an MDM2-p53 antagonist could favourably modulate its therapeutic index. The predicted short plasma half-life of ASTX295 should provide flexibility in controlling the duration of exposure in vivo, potentially enabling a more bone-marrow sparing approach to MDM2-p53 antagonism to be utilised. Citation Format: Elaine Willmore, Maria Ahn, Suzanne Kyle, Yan Zhao, Huw Thomas, Kenneth S. Rankin, Luke Bevan, Lynsey Fazal, Keisha Hearn, Nicola Wilsher, Justyna Kucia-Tran, Nicola Ferrari, Nicola Wallis, Neil Thompson, John Lyons, Duncan Miller, Celine Cano, Martin E. Noble, Ian R. Hardcastle, Steven Howard, Gianni Chessari, John Lunec, David R. Newell, Steve R. Wedge. Targeting the MDM2-p53 interaction: Time- and concentration-dependent studies in tumor and normal human bone marrow cells reveal strategies for an enhanced therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3333.
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Schenker, Adrian. "S. Schirone – R. Scognamiglio, Nessun altro debito che l’Amore. Prestito e usura nell’ Antico Testamento (Fondazione Antiusura San Nicola e Santi Medici-Bari), Rom (Ed. VIVERE IN) 1995, 122p., L. 9000; ISBN 88-083-5." Biblische Zeitschrift 44, no. 2 (April 5, 2000): 309. http://dx.doi.org/10.1163/25890468-04402031.
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Lippi, Lorenzo, Alessandro de Sire, Arianna Folli, Francesco D’Abrosca, Alessio Turco, Giuseppina Bonizzi, Nicola Fusco, and Marco Invernizzi. "Abstract P5-08-08: Ultrasound-guided injection with or without rehabilitation exercise in breast cancer survivors with sub-acromion-deltoid bursitis: a pilot randomized clinical study." Cancer Research 83, no. 5_Supplement (March 1, 2023): P5–08–08—P5–08–08. http://dx.doi.org/10.1158/1538-7445.sabcs22-p5-08-08.
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Abstract BACKGROUND: Due to the increasing overall survival of breast cancer (BC) patients, a growing interest has been raised in the current literature on disabling consequences of cancer and its treatment [1,2]. In particular, after radical surgery for BC, patients might frequently be affected by functional limitation of the shoulder joint, potentially related to the immobilization, surgical scar tensions, axillary web syndrome, subpectoral prostheses or expanders, or peripheral nerve damage [3]. In this scenario, several challenges are still open in the therapeutic approach to this disabling condition and the optimal management of shoulder dysfunction in breast cancer patients is far from being fully characterized. Therefore, the aim of this study was to assess the effects of a comprehensive rehabilitation program including ultrasound-guided injection of the sub-acromion deltoid bursa (SAD) followed by a rehabilitation exercise protocol in terms of feasibility, pain relief, upper limb function, quality of life, and safety. METHODS: In this study, we recruited consecutive breast cancer women referring to a Physical Medicine and Rehabilitation in Northern Italy and suffering from SAD bursitis in the absence of tendon lesions. Patients were assessed for eligibility and subsequently randomly assigned 1:1 to two groups. Group A received ultrasound-guided percutaneous injection of the SAD bursa (lidocaine and triamcinolone acetate) followed by a rehabilitation exercise program of 5 sessions lasting 1 hour each., while Group B received ultrasound-guided percutaneous injection only. Patients were assessed at baseline (T0), after a week (T1), and after 3 months (T2). The outcomes were numerical pain rating scale (NPRS), handgrip strength (HGS) test, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Oxford Shoulder Score (OSS), Global Perceived Effect (GPE), and safety. RESULTS: Thirty-seven patients were enrolled and randomly assigned to Group A (n=19; mean age: 56.05 ± 10.30 years; body mass index (BMI): 23.58 ± 2.79 kg/m2) and Group B (n=18; mean age: 58.39 ± 12.09 years; BMI: 22.72 ± 3.16 kg/m2). No major or minor adverse events were reported after this multidisciplinary intervention. Statistically significant within-group differences were found in both groups in terms of NPRS after the treatment (p < 0.05) and after the follow-up (p < 0.05). The between-group analysis showed significant differences in pain intensity (NRS: 2.16 ± 1.39 vs 4.78 1.77; p < 0.05), isometric muscle strength (25.11 3.20 vs 20.33 4.92; p< 0.001), shoulder function (OSS: 17.00 3.27 vs 33.11 6.471; p< 0.0001), and EORTC QLQ-C30 (Functional subscale: 88.74 7.71 vs 77.67 13.64; p=0.017; Symptom subscale: 11.43 8.56 vs 19.61 13.72; p=0.048; Global Health subscale: 79.36 13.72 vs 70.56 8.26; p=0.022) of the after the follow-up. However, no significant differences (p > 0.05) were reported at T1. CONCLUSION: Our findings showed that a comprehensive rehabilitation approach including ultrasound-guided injection combined with rehabilitation exercise might be safe, well-tolerated, and effective in breast cancer patients with SAD bursitis. These data emphasized the positive role of an interdisciplinary rehabilitation management in pain management and improving overall well-being of breast cancer patients. Further studies with larger samples and longer follow-ups are needed to confirm our data. REFERENCES: 1. Nardin S et al. Breast Cancer Survivorship, Quality of Life, and Late Toxicities. Front Oncol 2020, 10, 864. 2. D’Egidio V et al. Counseling interventions delivered in women with breast cancer to improve health-related quality of life: a systematic review. Qual Life Res 2017, 26, 2573-2592, doi:10.1007/s11136-017-1613-6. 3. Hidding JT et al. Treatment related impairments in arm and shoulder in patients with breast cancer: a systematic review. PLoS One. 2014 May 9;9(5):e96748. Citation Format: Lorenzo Lippi, Alessandro de Sire, Arianna Folli, Francesco D’Abrosca, Alessio Turco, Giuseppina Bonizzi, Nicola Fusco, Marco Invernizzi. Ultrasound-guided injection with or without rehabilitation exercise in breast cancer survivors with sub-acromion-deltoid bursitis: a pilot randomized clinical study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-08.
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Reduzzi, Carolina, Eleonora Nicolo, Lauren L. Ozimski, Marco Silvestri, Lorenzo Gerratana, Mara S. Serafini, Elisabetta Molteni, et al. "Abstract 3693: Molecular and functional characterization of circulating CK+/CD45+ cells in breast cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3693. http://dx.doi.org/10.1158/1538-7445.am2024-3693.
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Abstract Background: Circulating tumor cells (CTCs) are considered a key element in metastatic progression and represent a validated prognostic biomarker in breast cancer (BC). CTCs in BC are normally defined as epithelial cells (positive for EPCAM or cytokeratin, CK) lacking the expression of the leukocyte marker CD45. Circulating cells expressing both EPCAM/CK and CD45 (dual positive, DPcells) have however been reported in BC but not investigated. It is believed that DPcells derive from the heterotypic cell fusion of tumor and immune cells, but this hypothesis has not been demonstrated yet. We recently reported, for the first time, the association of DPcells with worse survival in a cohort of 341 BC patients (pts) [Reduzzi et al. ASCO 2022] supporting their tumor origin. Here, we further investigated their malignancy and metastatic potential by molecular profiling and functional experiments. Methods: The study consisted of 2 components: A) Single CTCs and DPcells were enriched from the blood of BC patients with the CellSearch platform, and isolated with the DEPArray system. Single cells underwent whole genome amplification and lowpass whole genome sequencing for single cell copy number alteration (CNA) profiling; B) DPcells and CTCs were investigated in the blood of immunodeficient (NSG) and immunocompetent (FVB) mouse models using various cell lines (LM2, 4T1, MVT1). To test their metastatic potential, DPcells from the primary tumor of FVB donor mice were transplanted into recipient NSG mice, and the metastatic burden in the lungs and liver quantified, in comparison with control CD45- tumor cells. Results: We analyzed 73 DPcells and 18 CTCs collected from 16 BC pts: Aberrant genomes were observed in 28% and 93% of evaluable cells, respectively. When collected from the same pt, CTCs showed clonal CNA profiles, while DPcells were highly heterogeneous. In vivo, DPcells could only be detected in the blood of FVB mice but not in NSG mice. They were very rare, comprising of only about 3% of the total CTC count. When DPcells and control tumor cells were isolated from the primary tumor of 10 donor mice and transplanted into the tail vein of 10 recipient mice, we observed no significant differences in the metastatic colonization of the lungs and liver by the two population, indicating that DPcells do in fact possess metastatic ability, and to a similar extent as control cancer cells. Conclusions: DPcells can have an aberrant genome, supporting their malignancy. Contrary to CTCs, DPcells’ CNA profiles are not clonal and, in vivo, they can only be observed in immunocompetent models; both observations support the tumor/immune fusion hypothesis. Finally, DPcells show metastatic potential in mice, in line with the association with worse survival we previously observed in BC pts. Overall DPcells seem a new CTC subpopulation that should not be neglected anymore. More studies are needed to better understand their origin and phenotypic/molecular features. Citation Format: Carolina Reduzzi, Eleonora Nicolo, Lauren L. Ozimski, Marco Silvestri, Lorenzo Gerratana, Mara S. Serafini, Elisabetta Molteni, Nadia Bayou, Amanda K. Strickland, Huiping Liu, Vera Cappelletti, Nicola Aceto, Massimo Cristofanilli. Molecular and functional characterization of circulating CK+/CD45+ cells in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3693.
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McBain, Kirsty, Gillian Lovell, Jasmine Trigg, Nicola Bevan, and Daniel Appledorn. "Abstract 4722: Enhanced phenotypic screening: A kinetic, multiplexed approach to analyzing drug effects using Incucyte® Live-Cell Analysis System." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4722. http://dx.doi.org/10.1158/1538-7445.am2024-4722.
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Abstract Phenotypic screening is a valuable tool for analysis of the complex mix of effects that drug treatment has on cells. Traditionally image-based screening uses fixed cells stained with reagents at a pre-chosen end point, however our technique combines kinetic, label-free readouts with non-perturbing fluorescence reporters to enable information-rich quantification of compound effects. A549 lung cancer cells were treated with a library of over 800 FDA-approved drugs while images were acquired in the Incucyte® Live-Cell Analysis System every two hours for four days. Cell growth and viability were measured using label-free readouts of confluence and dead cell count while cell cycle, cell death and Akt pathways were investigated using multiplexed fluorescent readouts. Cytotoxicity was measured using label-free Incucyte® AI Cell Health Analysis Software Module which uses two neural networks to segment individual cells and classify them as live or dead. Assay robustness was quantified using the time course of positive and negative controls (camptothecin and vehicle, respectively). Z’ reached a maximal value >0.9 between 48h and 72h; at 72h 4.4% of the compounds within the library induced >50% cell death. Correlation between % Live cells and % Confluence indicated 3 types of effect: cytotoxic (low viability, low confluence), cytostatic (high viability, low confluence), and none (high viability, high confluence). Morphological changes were observed in a multitude of wells with 29 compounds inducing cell enlargement >1800 µm2, suggesting induction of senescence. Hits from fluorescent readouts were identified as the compounds which perturbed the quantified readout more than 3 standard deviations away from the mean value of the vehicle. Mechanisms of cell death were examined by correlative analysis of the total dead cell population (label-free cell death identification), caspase-active (caspase 3/7-reagent positive) and Annexin V positive cells. This enabled rapid identification of compounds which induced apoptosis by caspase-independent pathways, including the serotonin-selective reuptake inhibitor Sertraline. Kinetic plots of cell cycle stage (% S|G2|M or G1) revealed contrasting mechanisms. Mycophenolic acid induced cell cycle arrest, observed as a consistent increase in the percentage of cells in G1 over time. However flumazenil displayed repeated, transient peaks in the percentage of cells in S|G2|M over the same 72h period, indicating synchronisation behavior. Incucyte® Live-Cell Analysis System as a phenotypic screening platform provides valuable kinetic data from cells within the physiologically relevant environment of a standard incubator. Label-free readouts yield direct cellular information and can be combined with fluorescent data to provide vastly more information than a single endpoint readout. Citation Format: Kirsty McBain, Gillian Lovell, Jasmine Trigg, Nicola Bevan, Daniel Appledorn. Enhanced phenotypic screening: A kinetic, multiplexed approach to analyzing drug effects using Incucyte® Live-Cell Analysis System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4722.
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Vetter, Marcus, Bich Doan Ngyuen-Sträuli, Ilona Krol, Alexander Ring, Angela Kohler, Francesc Castro-Giner, Maren Vogel, et al. "Abstract PO5-18-04: Effect of Digoxin on clusters of circulating tumor cells in patients with metastatic breast cancer (DICCT)." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO5–18–04—PO5–18–04. http://dx.doi.org/10.1158/1538-7445.sabcs23-po5-18-04.
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Abstract Background: The presence of circulating tumor cell (CTC) clusters is associated with tumor progression and with a bad prognosis in various cancer types1,2. In breast cancer, a pre-clinical model demonstrated that Na/K-ATPase inhibitors such as digoxin could dissolve CTC clusters and reduce metastasis3. DICCT is a single-arm, therapeutic exploratory phase I study aimed to examine whether digoxin can disrupt CTC clusters in metastatic breast cancer patients (NCT03928210). Material and methods: Metastatic breast cancer patients in whom clusters of CTCs have been detected were eligible. Patients with concomitant heart disease were excluded. After progressive disease in any line of therapy, a window of opportunity before initiation of subsequent systemic therapy was used to administer digoxin treatment for seven (7) days. For CTC detection, blood samples were processed with the FDA-cleared Parsortix system (ANGLE plc, UK). Captured CTCs were stained for EPCAM, HER2, EGFR (positive CTC selection) and CD45 (exclusion marker). To gain insight into the cluster-dissolution ability of digoxin, the primary endpoint was size of CTC clusters (i.e. number of cells within each cluster) under digoxin therapy. The cumulative effect of digoxin treatment on the primary endpoint was assessed by a linear regression model. Results: Nine (9) patients with CTC clusters detected at baseline were enrolled. A target level of digoxin above 0.7 ng/ml could be confirmed at day 7 for all patients. For quantitative and qualitative analysis of CTC clusters, 5.5 to 27 ml of blood were analyzed at baseline, at day 0 pre-treatment, and post 2 hours, 3 days and 7 days of digoxin treatment. The average cluster size ranged between 2 and 11.8 cells (median 2.9) considering all samples from all patients. Digoxin treatment reduced cluster size in 8 patients (88.9%) to different extents, and the proportion of CTC cluster over single CTCs was also reduced in 6 patients (66.7%). The effect of digoxin was evident in both homotypic (cancer cells only) and heterotypic (aggregates of CTCs and white blood cells) clusters. The treatment was well tolerated, and no adverse events related to the study treatment occurred. All patients completed the treatment according to the protocol. Conclusion: DICCT provides the first-in-human proof-of-principle that digoxin induces a partial dissolution of CTC clusters in patients with metastatic breast cancer at drug levels that are safe and well tolerated. Conceptualization of follow-up trials including Na/K-ATPase inhibitors and patient outcome endpoints are underway. References: 1. Ring A, Nguyen-Strauli BD, Wicki A, Aceto N. Biology, vulnerabilities and clinical applications of circulating tumour cells. Nat Rev Cancer 2022:1-17. DOI: 10.1038/s41568-022-00536-4. 2. Schuster E, Taftaf R, Reduzzi C, Albert MK, Romero-Calvo I, Liu H. Better together: circulating tumor cell clustering in metastatic cancer. Trends Cancer 2021;7(11):1020-1032. DOI: 10.1016/j.trecan.2021.07.001. 3. Gkountela S, Castro-Giner F, Szczerba BM, et al. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell 2019;176(1-2):98-112 e14. DOI: 10.1016/j.cell.2018.11.046. Citation Format: Marcus Vetter, Bich Doan Ngyuen-Sträuli, Ilona Krol, Alexander Ring, Angela Kohler, Francesc Castro-Giner, Maren Vogel, Cvetka Grasic Kuhar, Fabienne Schwab, Viola Heinzelmann-Schwarz, Gabriela Kuster Pfister, Walter Weber, Christian Kurzeder, Nicola Aceto. Effect of Digoxin on clusters of circulating tumor cells in patients with metastatic breast cancer (DICCT) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-04.
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Lippi, Lorenzo, Alessandro de Sire, Antonio Ammendolia, Carlo Cisari, Konstantinos Venetis, Elham Sajjadi, Nicola Fusco, and Marco Invernizzi. "Abstract P4-10-15: Whole-body vibration combined with physical exercise to treat aromatase inhibitor-induced musculoskeletal symptoms in breast cancer women: Results of a pilot randomized controlled study." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–10–15—P4–10–15. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-10-15.
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Abstract BACKGROUND. Aromatase inhibitors (AIs) represent a cornerstone of hormone receptor (HR)-positive breast cancers management. However, AIs-induced musculoskeletal symptoms (AIMSS) might be frequently reported during estrogen depletion, with a crucial impact on cancer treatment adherence [1-2]. To date, physical exercise has been proposed as a promising therapeutic intervention to improve symptoms in AIMSS breast cancer patients [3] and recently, also whole-body vibration (WBV) showed promising results in these women. WBV is an effective neuromuscular training proposed to enhance muscle function and proprioception through various frequencies of mechanical vibration inducing repetitive muscle contractions. However, at present, data about tailored and effective multimodal rehabilitative exercise protocols to treat AIMSS are still controversial [3]. Therefore, this pilot randomized controlled study aimed at assessing the safety and efficacy of WBV in breast cancer women suffering from AIMSS. METHODS: In this study we recruited adults women undergoing AIs treatment for breast cancer and suffering from AIMSS. Twentytwo patients were enrolled and subsequently randomly assigned 1:1 to two groups. Group A received physical exercise and WBV, while Group B received physical exercise combined with sham WBV. The patients were assessed at the baseline (T0) and after 4 weeks of treatment (T1). The primary endpoint was the numerical pain rating scale (NPRS) for pain assessment; the secondary endpoints were the handgrip strength (HGS) test to assess appendicular muscle strength, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to assess pain, joint stiffness, and function; 10-meter walking test (10MWT) and 6MWT to evaluate physical performance; the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) to assess function, symptoms, and global health. RESULTS: Group A (n=11; mean age: 51.73±10.73 years; body mass index (BMI): 25.56±5.17 kg/m2) showed a statistically significant improvement of pain (NPRS: 6.82±1.17 vs 5.73±1.01; p=0.031). In contrast, patients in Group B, control group, (n=11; mean age: 58.55±9.71 years; BMI: 27.31±3.84 kg/m2), did not significantly improved in terms of pain (NPRS: 6.91±2.02 vs 5.91±2.51; p=0.07). Moreover, significant differences between groups at T1 were found in terms of WOMAC physical functioning (Group A: 77.56±9.853; Group B: 65.63±14.27; p=0.044). Furthermore, a significant improvement in terms of muscle strength, physical performance and quality of life (EORTC QLQ-C30) were reported in intragroup analysis in both groups, without significant differences between groups. We did not register dropouts or side effects in both groups. Lastly, both patients and the physical therapist reported a high level of satisfaction about the rehabilitative intervention performed. CONCLUSION: These findings showed that physical exercise and WBV combination therapy might be safe, well-tolerated and effective in patients with AIMSS. However, further studies are warranted to assess long terms effects of this combined rehabilitative treatment. REFERENCES: 1. Molehin D, Rasha F, Rahman RL, Pruitt K. Regulation of aromatase in cancer. Mol Cell Biochem. 2021. 2. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat. 2012;134(2):459-78. 3. Roberts KE, Rickett K, Feng S, Vagenas D, Woodward NE. Exercise therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer. Cochrane Database Syst Rev. 2020;1:CD012988. Citation Format: Lorenzo Lippi, Alessandro de Sire, Antonio Ammendolia, Carlo Cisari, Konstantinos Venetis, Elham Sajjadi, Nicola Fusco, Marco Invernizzi. Whole-body vibration combined with physical exercise to treat aromatase inhibitor-induced musculoskeletal symptoms in breast cancer women: Results of a pilot randomized controlled study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-15.
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Kirkland, James. "IRVING S. WRIGHT AWARD, VINCENT CRISTOFALO AWARD, AND TERRIE FOX WETLE AWARD PRESENTATIONS AND LECTURES." Innovation in Aging 6, Supplement_1 (November 1, 2022): 162. http://dx.doi.org/10.1093/geroni/igac059.647.
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Abstract The Irving S. Wright Award of Distinction Lecture will feature an address by the 2022 recipient Thomas M. Gill, MD of Yale University. The Vincent Cristofalo Rising Star Award in Aging Research lecture will feature an address by the 2022 recipient Jamie Nicole Justice, PhD, of Wake Forest University. The Terrie Fox Wetle Award lecture will feature an address by the 2022 recipient Benjamin H. Han, MD, MPH, of the University of California San Diego. These awards are given by the American Federation for Aging Research, Inc.
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Sulleza, Vilma S., and Ronaldo F. Frufonga. "Establishment of a Migrant Community: The Story of the Jamahs in San Nicolas, La Paz, Iloilo City." Proceedings Journal of Interdisciplinary Research 2 (October 10, 2015): 177–83. http://dx.doi.org/10.21016/irrc.2015.ju24wf52o.
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This study was conceptualized to reconstruct the history of the Muslims in Iloilo City who attend worship at the San Nicolas mosque. The study employed the descriptive case study method. The in-depth and semi-structured interviews were the main tools. Other tools were informal and direct observations and focus group discussions. Inconsistencies in the narratives were straightened out in the focus group discussion. The key informants were five Maranao Muslim males from Marawi City. Reasons for migration are mostly economic and majorities are traders from Lanao Del Sur. In the 1970’s more migrants came most were single young males to avoid the then conflict between the Muslim rebels and the government troops during the Martial Law. All of the first generation migrants are males, the wives and female children followed once the males had established themselves. There were no concrete problems they have encountered as a community. The second and third generations have already adapted to the Ilonggo lifestyle. In general, they encountered no resistance from the Ilonggos, they feel accepted. They have no recollection of stories of resistance from the first generation migrants either.
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Stanton, Sasha E., Lisa D. MacDonald, Stephan Fiset, Staci Mellinger, Nicole Moxon, Heather Hirsch, Tracy L. Kelly, Kristina H. Young, and David B. Page. "Abstract OT2-20-01: Neoadjuvant survivin immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor positive (HR+) early-stage breast cancer." Cancer Research 83, no. 5_Supplement (March 1, 2023): OT2–20–01—OT2–20–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-ot2-20-01.
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Abstract Background: HR+ early stage breast cancer (ESBC) is associated with suboptimal pathologic complete response rate (pCR, ~10%) following neoadjuvant cytotoxic chemotherapy. Neoadjuvant endocrine therapy with aromatase inhibitors (AI) may serve as an effective alternative as gauged using the surrogate Ki67 cell proliferation histologic marker. Patients with poor Ki67 response (defined as Ki67>10%) following neoadjuvant AI exhibit poor prognosis and therapeutic resistance to both endocrine therapy and chemotherapy. In a genomic analysis of Ki67-high HR+ tumors, we identified 8-fold upregulation of BIRC5 (survivin), a gene that regulates apoptosis and the cell cycle and is associated with poor clinical outcome. Maveropepimut-S (MVP-S) leverages the non-aqueous, lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from Survivin. Treatment with MVP-S and intermittent, low-dose cyclophosphamide (CPA) has shown to increase tumor infiltration of survivin-specific T cells. Previous clinical trials have shown that MVP-S is well-tolerated, immunogenic, and could lead to clinical response in several cancer indications. Further exploration of the regimen in breast cancer could extend the application of this immunotherapy for the unmet medical need of improving clinical response in high ki67 HR+ ESBC prior to surgery. Trial Design: NCT04895761 is phase I trial evaluating the safety and immunologic effects of neoadjuvant MVP-S plus letrozole (arm A, n=6), with/without tumor-directed MR-guided radiotherapy (arm B, n=6), or intermittent low-dose cyclophosphamide (CPA, arm C, n=6). Postmenopausal patients with T1c+ HR+HER2- breast cancer with Ki67>10% will receive two doses of MVP-S and 7 weeks of neoadjuvant letrozole prior to surgery (all arms), arm B will be treated additionally with concurrent 10Gy x 2 tumor boost radiation to facilitate immunogenic cell death, and arm C (n=6) will be treated additionally with intermittent low-dose CPA (50mg BID) to facilitate regulatory T cell depletion. Specific Aims: The primary objective is safety. Biomarker objectives are to evaluate for each treatment arm: 1) systemic type I survivin-specific immune response, as measured by IFN-γ ELISPOT; 2) changes in immune environment by GeoMx digital spatial genomic profiling; 3) and changes in tumor infiltrating lymphocytes (TILs) and Ki67. These data will be used to identify the most immunogenic MVP-S combination therapy for study in phase II trial powered to assess clinical outcome (pCR). Accrual: 3 of 6 patients in the MVP-S+ letrozole arm have been enrolled. Arm B and C will enroll after completion of arm A. Citation Format: Sasha E. Stanton, Lisa D. MacDonald, Stephan Fiset, Staci Mellinger, Nicole Moxon, Heather Hirsch, Tracy L. Kelly, Kristina H. Young, David B. Page. Neoadjuvant survivin immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor positive (HR+) early-stage breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-20-01.
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John, Bincy, Christopher Currie, Nicole Westrick, Tyler Rowe, Andrew Wong, Elizabeth Rainbolt, Zachary Ward, Chassidy Hall, and David Harris. "Abstract 2841: Development and validation of a systemic human multiple myeloma model utilizing luciferase expressing MM1.S tumor cells." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2841. http://dx.doi.org/10.1158/1538-7445.am2024-2841.
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Abstract Multiple Myeloma (MM) is a complex hematologic malignancy characterized by clonal proliferation of transformed plasma cells leading to overproduction of monoclonal immunoglobulins and subsequently end-stage organ damage. Despite therapeutic advances, MM is an incurable disease with poor prognosis in high-risk patients, and thus relevant preclinical models are necessary to develop novel treatment strategies. We developed a Multiple Myeloma in vivo model by systemic implantation of the luciferase-expressing glucocorticoid sensitive tumor cell line MM1.S (MM1.S-Luc) into immunodeficient NCG mice. First, we generated a MM1.S-Luc monoclonal cell line from a polyclonal pool of stable luciferase-expressing cells by limiting dilution. Single cells from the stable pool were expanded under selective pressure and four MM1.S-Luc monoclonal lines were selected based on in vitro growth properties and bioluminescence intensity. Next, we determined the in vivo tumor growth profile by testing the monoclonal lines at two different cell inoculums, and disease progression was monitored by in vivo serial bioimaging. MM1.S-Luc tumor growth kinetics revealed a long latency and based on our in vivo imaging results, the tumor preferentially localized to the long bones, lungs, and mandible. For validation of the MM1.S-Luc in vivo model, we determined the efficacy and survival benefit in response to various clinically relevant standard of care agents including Dexamethasone, Daratumumab, Cyclophosphamide, Vincristine, Panobinostat, and Bortezomib. The quantification of tumor burden by bioluminescent imaging showed reduced tumor burden and prolonged survival with Panobinostat and Cyclophosphamide. In summary, we have developed a systemic MM1.S-Luc model that recapitulates the disease dissemination and invasiveness of multiple myeloma for evaluating novel therapeutic approaches to treatment. Citation Format: Bincy John, Christopher Currie, Nicole Westrick, Tyler Rowe, Andrew Wong, Elizabeth Rainbolt, Zachary Ward, Chassidy Hall, David Harris. Development and validation of a systemic human multiple myeloma model utilizing luciferase expressing MM1.S tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2841.
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Harwood, Dylan, Vilde Pedersen, Nicolai S. Bager, Ane Y. Schmidt, Tobias O. Stannius, Ausrine Areskeviciute, Knud Josefsen, et al. "Abstract 1144: Glioblastoma cells increase expression of neurodevelopmental programs and synaptic connectivity in the tumor periphery." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1144. http://dx.doi.org/10.1158/1538-7445.am2024-1144.
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Abstract Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by concomitant and adjuvant temozolomide chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the brain parenchyma, where they give rise to the recurrent tumor. Based on gene expression, the tumor core can be subtyped into mesenchymal, proneural and classical areas, each being associated with differences in genetic alterations and cellular composition. In contrast, the tumor periphery where migrating tumor cells infiltrate brain parenchyma is less characterized in patients. Using spatial transcriptomics (n = 11), we show that specific malignant states colocalize in tumor core areas with necrosis and microvascular proliferation. Malignant cells within proneural or mesenchymal subtyped cores displayed, as expected, many differences in genetic expression, although such differences disappeared in the tumor periphery. Malignant cells residing in the tumor periphery had increased expression of genes related to neurodevelopmental pathways and synaptic connectivity. Our findings show similarities in cellular states across tumor subtypes with implications for post-operative treatment and provide an updated view of the spatial landscape of glioblastomas. Citation Format: Dylan Harwood, Vilde Pedersen, Nicolai S. Bager, Ane Y. Schmidt, Tobias O. Stannius, Ausrine Areskeviciute, Knud Josefsen, Dorte S. Nørøxe, David Scheie, Hannah E. Rostalski, Ulrik Lassen, Frederik O. Bagger, Joachim Weischenfeldt, Dieter H. Heiland, Kristoffer Vitting-Seerup, Signe R. Michaelsen, Bjarne W. Kristensen. Glioblastoma cells increase expression of neurodevelopmental programs and synaptic connectivity in the tumor periphery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1144.
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Andrade-Gómez, L., C. D. Pinacho-Pinacho, J. S. Hernández-Orts, A. L. Sereno-Uribe, and M. García-Varela. "Morphological and molecular analyses of a new species of Saccocoelioides Szidat, 1954 (Haploporidae Nicoll, 1914) in the fat sleeper Dormitator maculatus (Bloch) (Perciformes: Eleotridae) from the Gulf of Mexico." Journal of Helminthology 91, no. 4 (July 26, 2016): 504–16. http://dx.doi.org/10.1017/s0022149x1600047x.
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AbstractSaccocoelioides olmecae n. sp. is described from specimens recovered from the intestine of the fat sleeper Dormitator maculatus (Bloch) (Perciformes: Eleotridae) collected in six localities along the coast of the Gulf of Mexico. The new species is mainly distinguished from the other three described species of Saccocoelioides Szidat, 1954 from North and Middle America (i.e. S. sogandaresi Lumsden, 1963, S. chauhani Lamothe-Argumedo, 1974 and S. lamothei Aguirre-Macedo & Violante-González, 2008) by having an elongated body, a sac-like caecum, a uterus that extends to the first third of body and by having vitelline follicles longitudinally elongated reaching the posterior end of the body. Sequences of the large subunit (LSU) of the ribosomal DNA, including the domain D1–D3, and the internal transcribed spacer 2 (ITS2) were used independently and concatenated to corroborate the morphological distinction among S. olmecae n. sp., S. chauhani and S. lamothei from freshwater and brackish-water fish from Middle America. The genetic divergence estimated among the three species of Saccocoelioides was very low: 1% for LSU and from 1 to 4% for ITS2. Maximum likelihood and Bayesian inference analyses for each dataset and both datasets combined revealed that S. olmecae n. sp. represents an independent clade with moderate bootstrap support and posterior probabilities. This is the third species of Saccocoelioides described in Mexico, and the 17th species from the Americas.
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Cook, Ashley L., ojit Sur, Laura Dobbyn, Evangeline Watson, Joshua D. Cohen, Blair Ptak, Bum Seok Lee, et al. "Abstract 2082: Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2082. http://dx.doi.org/10.1158/1538-7445.am2024-2082.
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Abstract Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen revealed disruption of kinase SMG1’s phosphorylation of UPF1 as a potent disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases. Citation Format: Ashley L. Cook, ojit Sur, Laura Dobbyn, Evangeline Watson, Joshua D. Cohen, Blair Ptak, Bum Seok Lee, Suman Paul, Emily Hsiue, Maria Popoli, Bert Vogelstein, Nickolas Papadopoulos, Chetan Bettegowda, Kathy Gabrielson, Shibin Zhou, Kenneth Kinzler, Nicolas Wyhs. Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2082.
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Matarazzo, Maria Gabriella. "ultima opera di Malvasia: 'Il Claustro di S. Michele in Bosco' e la decorazione carraccesca tra finzione e verità." Acta ad archaeologiam et artium historiam pertinentia 32, no. 18 N.S. (September 13, 2021): 29–58. http://dx.doi.org/10.5617/acta.9018.
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The Carracci's decorative vocabulary (from the early Bolognese friezes to the cycles of the Farnese Gallery in Rome and of the Cloister of San Michele in Bosco in Bologna) made extensive use of anthropomorphic supports, especially telamons and terms. Painted with a monochromatic technique, they deceived the beholder for their effective imitation of marble sculptures that illusively jut from the surface of the wall. While art historical scholarship mainly discussed them in regard to their chronology, attribution, iconography and their relationship with the Cinquecento decoration systems, their early reception still lacks a comprehensive assessment. This essay aims to undertake it through the case study of Il Claustro di S. Michele in Bosco, the last art-historical work by Malvasia. A section of this booklet is dedicated to the chiaroscuro"Termini" flanking the episodes of the life of St. Benedict painted by Ludovico Carracci and his pupils in the cloister of the Bolognese Olivetan monastery. Giacomo Giovannini, the engraver to whom Malvasia commissioned the illustrations included in the volume, also reproduced these painted sculptures in four etchings. By referring to a central couplet from the famous sonnet by Agostino Carracci "in lode di Nicolò Bolognese", he characterized Ludovico's (and Reni's) telamons as Michelangiolesque in their contour and Tizianesque in their naturalezza, as opposed to Annibale's terms frescoed in the Farnese Gallery, whose style Malvasia considered too harsh and dry ("statuino"). In this essay, Malvasia's notes on the cloister's telamons will be compared to his previous critical works and will be contextualized within the seventeenth-century Literature of Art and the coeval reproductive printmaking. As I will demonstrate, Malvasia aimed to restore the central role played by Agostino and Ludovico in the renovation of this decorative style, a role that was obscured by Annibale's growing fame in this genre of painting, particularly driven by the prints after his frescoes in the Farnese Palace published in the second half of the seventeenth century. On cover:ANNIBALE CARRACCI (BOLOGNA 1560 - ROME 1609), An Allegory of Truth and Time c. 1584-1585.Oil on canvas | 130,0 x 169,6 cm. (support, canvas/panel/str external) | RCIN 404770Royal Collection Trust / © Her Majesty Queen Elizabeth II 2021.
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Grible, Jacqueline M., Tess Leftwich, Amy L. Olex, Alex K. Duong, Nicole Hairr, Narmeen S. Rashid, Timothy M. Smith, et al. "Abstract P3-09-06: Targeting tumor subpopulations based on single-cell transcriptomics." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–09–06—P3–09–06. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-09-06.
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Abstract Breast cancers that are hormone receptor negative, such that they do not express the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), are known as triple-negative breast cancer (TNBC), and are predominantly of the basal-like subtype. These tumors aggressively metastasize, have limited effective therapeutic options, and are prevalent in patients of African descent. In these studies, we utilized a racially diverse set of 21 breast cancer patient-derived xenografts (PDXs) and 6 cell lines to identify new therapeutic combinations that may exhibit increased efficacy for patients based on ancestral heritage. Tumor subpopulation abundance was measured by single-cell RNA-sequencing (scRNAseq) a set of 13 PDXs, including some that had been subjected to long term carboplatin treatment or endocrine therapy in vivo. We identified two to four major cell types per PDX and sought to integrate this information with cytotoxic high throughput screens (HTS) of 516 clinically actionable agents. Among several interesting and overlapping findings from these multiscale models, BIRC5 (Survivin) was identified as a readily actionable target in the proliferative component of all TNBC models assayed. Analysis of public datasets found that BIRC5 expression in TNBC patient tumors was significantly correlated with reduced metastasis-free survival. In vitro and in vivo studies from our group and others found that YM155, which targets Survivin, was highly cytotoxic towards breast cancer cells. YM155 has been previously safely administered in Phase I/II clinical trials. To uncover putative dependency pathways that may be exploited to prevent acquired resistance to BIRC5 (Survivin) inhibition, we performed synergistic HTS assays whereby the efficacy of our 516 therapeutic library was assessed in the presence versus absence of YM155. Those drugs which were found to be more highly effective when given in combination with YM155 were then selected for ongoing in vitro and in vivo applications. Grant ID: 1R01CA246182-01A1 (NIH/NCI), CCR19608826 (Susan G. Komen Foundation), VCU School of Medicine VETAR, the Jeffress Trust, UL1TR002649 (CTSA/NCATS) Citation Format: Jacqueline M Grible, Tess Leftwich, Amy L Olex, Alex K Duong, Nicole Hairr, Narmeen S Rashid, Timothy M Smith, Lia Signaevskaia, David C Boyd, Mikhail G Dozmorov, Joshua C Harrell. Targeting tumor subpopulations based on single-cell transcriptomics [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-06.
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Boyd, David, and Chuck Harrell. "Abstract P1-13-04: Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers." Cancer Research 83, no. 5_Supplement (March 1, 2023): P1–13–04—P1–13–04. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-13-04.
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Abstract Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers David C. Boyd1,2, Amy L. Olex3, Tess Leftwich1, Nicole Hairr1, Alex K. Duong1, Narmeen S. Rashid1,3, Mohammad A Alzubi1,2, Holly Byers1, Aaron D. Valentine1, Julia E. Altman1, Emily Zboril1, Jacqueline M. Grible1, Madelyn Esquivel1, Scott A. Turner1, Andrea Ferreira-Gonzalez1, Mikhail G. Dozmorov5, J. Chuck Harrell1,2,6 1Department of Pathology, Virginia Commonwealth University; 2Integrative Life Sciences Program, VCU; 3Wright Center for Clinical and Translational Research, VCU; 4Department of Biology, University of Richmond; 5Department of Biostatistics, VCU; 6Massey Cancer Center, VCU. There is an urgent need for new therapeutic options for basal-like Triple Negative Breast Cancers (TNBC). To mirror the NCI-ComboMATCH study, and identify new synergistic drug combinations, we analyzed a set of 20 breast cancer patient-derived xenografts and 14 cell lines to identify targetable targets in each model. The Oncomine Comprehensive Assay v3 was performed to assess 161 genes for hotspot mutations, focal copy number variants, amplification/deletions, and RNA-fusion genes. Next, each PDX and their isogenic drug-resistant sublines were analyzed with bulk RNA-sequencing (217 samples) and cell single-cell RNA-sequencing (~100,000 cells). Of all NCI-MATCH defined targetable mutations, 37% of the models contained pathogenic PIK3CA amplifications or mutations. PIK3CA is one of the most common oncogenic aberrations identified in patients and the PI3K pathway is overactive in the majority of TNBCs, therefore we sought to target it across all models and identify the most efficacious synergistic drug partner. Short-term cultures of each PDX model were screened with a library of >1,000 FDA-approved/experimental drugs to identify compounds that were cytotoxic. Synergistic drug screens were then performed with each drug in combination with the PI3K inhibitor byl-719 (alpelisib) a current standard-of-care drug used for PI3K mutant ER+ disease. Synergism was identified using coefficient of drug interaction (CDI) calculations and 10 drugs were identified as synergistic across several models. Using several criteria, including clinical status and pathway analysis, 3 drugs were selected for CompuSyn-based synergism testing and each was confirmed to be synergistic in vitro. Testing with in vivo models of each drug combination has thus far confirmed that each is synergistic per CDI metrics. Those combinations are currently being tested for efficacy in the metastatic setting with a set of basal-like PDXs. Citation Format: David Boyd, Chuck Harrell. Potentiating Alpelisib in PI3K Pathway Overactive Triple Negative Breast Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-04.
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Zboril, Emily Kate, Julia E. Altman, Nicole S. Hairr, Rachel K. Myrick, Amy L. Olex, Mikhail G. Dozmorov, and J. Chuck Harrell. "Abstract 6269: Assessment of new generation endocrine therapies for the treatment of breast to bone metastasis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6269. http://dx.doi.org/10.1158/1538-7445.am2024-6269.
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Abstract Estrogen receptor (ER) signaling is the main driver of tumorigenesis in ER+ breast cancers by inducing proliferation and survival through genomic and non-genomic means, therefore inhibition of ER signaling has been a mainstay of treatment for decades. Roughly 30 percent of patients will develop treatment-refractory recurrence or metastasis within their lifetime, which may include metastasis to the bone, lung, liver, and brain. Although advances in treatment approaches have prolonged average progression free survival, metastatic breast cancer remains incurable. A new endocrine therapy, Elacestrant, has been approved by the FDA for the treatment of ER+, ESR1-mutant advanced or metastatic breast cancer. The mechanism of action of Elacestrant involves both degradation of ER and modulation of ER signaling through non-degradative means. The central hypothesis of this study was that Elacestrant may prolong progression free survival in animal models of breast to bone metastasis, because modulation of ER in the bone would decrease the incidence of osteoporosis which is induced by other endocrine therapies. However, we discovered that prolonged Elacestrant treatment induces destruction of the trabecular bone structure and increased adipocyte mass within the bone, consistent with an osteoporotic phenotype. Ongoing studies will seek to determine if other endocrine therapies will provide better protection to the bone architecture while reducing metastatic burden in animal models. Additionally, we will evaluate organotropic efficacy of new endocrine therapies on multi-organ metastasis to determine if utility is contingent upon the metastatic site. Citation Format: Emily Kate Zboril, Julia E. Altman, Nicole S. Hairr, Rachel K. Myrick, Amy L. Olex, Mikhail G. Dozmorov, J. Chuck Harrell. Assessment of new generation endocrine therapies for the treatment of breast to bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6269.
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KITLV, Redactie. "Book Reviews." New West Indian Guide / Nieuwe West-Indische Gids 73, no. 1-2 (January 1, 1999): 121–81. http://dx.doi.org/10.1163/13822373-90002590.
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-Charles V. Carnegie, W. Jeffrey Bolster, Black Jacks: African American Seamen in the age of sail. Cambridge MA: Harvard University Press, 1997. xiv + 310 pp.-Stanley L. Engerman, Wim Klooster, Illicit Riches: Dutch trade in the Caribbean, 1648-1795. Leiden: KITLV Press, 1998. xiv + 283 pp.-Luis Martínez-Fernández, Emma Aurora Dávila Cox, Este inmenso comercio: Las relaciones mercantiles entre Puerto Rico y Gran Bretaña 1844-1898. San Juan: Editorial de la Universidad de Puerto Rico, 1996. xxi + 364 pp.-Félix V. Matos Rodríguez, Arturo Morales Carrión, Puerto Rico y la lucha por la hegomonía en el Caribe: Colonialismo y contrabando, siglos XVI-XVIII. San Juan: Editorial de la Universidad de Puerto Rico y Centro de Investigaciones Históricas, 1995. ix + 244 pp.-Herbert S. Klein, Patrick Manning, Slave trades, 1500-1800: Globalization of forced labour. Hampshire, U.K.: Variorum, 1996. xxxiv + 361 pp.-Jay R. Mandle, Kari Levitt ,The critical tradition of Caribbean political economy: The legacy of George Beckford. Kingston: Ian Randle, 1996. xxvi + 288., Michael Witter (eds)-Kevin Birth, Belal Ahmed ,The political economy of food and agriculture in the Caribbean. Kingston: Ian Randle; London: James Currey, 1996. xxi + 276 pp., Sultana Afroz (eds)-Sarah J. Mahler, Alejandro Portes ,The urban Caribbean: Transition to the new global economy. Baltimore: John Hopkins University Press, 1997. xvii + 260 pp., Carlos Dore-Cabral, Patricia Landolt (eds)-O. Nigel Bolland, Ray Kiely, The politics of labour and development in Trinidad. Barbados, Jamaica, Trinidad and Tobago: The Press University of the West Indies, 1996. iii + 218 pp.-Lynn M. Morgan, Aviva Chomsky, West Indian workers and the United Fruit Company in Costa Rica, 1870-1940. Baton Rouge: Louisiana State University Press, 1996. xiii + 302 pp.-Eileen J. Findlay, Maria del Carmen Baerga, Genero y trabajo: La industria de la aguja en Puerto Rico y el Caribe hispánico. San Juan: Editorial de la Universidad de Puerto Rico, 1993. xxvi + 321 pp.-Andrés Serbin, Jorge Rodríguez Beruff ,Security problems and policies in the post-cold war Caribbean. London: :Macmillan; New York: St. Martin's, 1996. 249 pp., Humberto García Muñiz (eds)-Alex Dupuy, Irwin P. Stotzky, Silencing the guns in Haiti: The promise of deliberative democracy. Chicago: University of Chicago Press, 1997. xvi + 294 pp.-Carrol F. Coates, Myriam J.A. Chancy, Framing silence: Revolutionary novels by Haitian women. New Brunswick NJ: Rutgers University Press, 1997. ix + 200 pp.-Havidán Rodríguez, Walter Díaz, Francisco L. Rivera-Batiz ,Island paradox: Puerto Rico in the 1990's. New York: Russel Sage Foundation, 1996. xi + 198 pp., Carlos E. Santiago (eds)-Ramona Hernández, Alan Cambeira, Quisqueya la Bella: The Dominican Republic in historical and cultural perspective. Armonk NY: M.E. Sharpe, 1996. xi + 272 pp.-Ramona Hernández, Emilio Betances ,The Dominican Republic today: Realities and perspectives. New York: Bildner Center for Western Hemisphere studies, CUNY, 1996. 205 pp., Hobart A. Spalding, Jr. (eds)-Bonham C. Richardson, Eberhard Bolay, The Dominican Republic: A country between rain forest and desert. Wekersheim, FRG: Margraf Verlag, 1997. 456 pp.-Virginia R. Dominguez, Patricia R. Pessar, A visa for a dream: Dominicans in the United States. Boston: Allyn and Bacon, 1995. xvi + 98 pp.-Diane Austin-Broos, Nicole Rodriguez Toulis, Believing identity: Pentecostalism and the mediation of Jamaican ethnicity and gender in England. Oxford NY: Berg, 1997. xv + 304 p.-Mary Chamberlain, Trevor A. Carmichael, Barbados: Thirty years of independence. Kingston: Ian Randle Publishers, 1996. xxxv + 294 pp.-Paul van Gelder, Gert Oostindie, Het paradijs overzee: De 'Nederlandse' Caraïben en Nederland. Amsterdam: Bert Bakker, 1997. 385 pp.-Roger D. Abrahams, Richard D.E. Burton, Afro-Creole: Power, Opposition, and Play in the Caribbean. Ithaca NY: Cornell University Press, 1997. x + 297 pp.-Roger D. Abrahams, Joseph Roach, Cities of the dead: Circum-Atlantic performance. New York NY: Columbia University Press, 1996. xiii + 328 pp.-George Mentore, Peter A. Roberts, From oral to literate culture: Colonial experience in the English West Indies. Kingston, Jamaica: The Press University of the West Indies, 1997. xii + 301 pp.-Emily A. Vogt, Howard Johnson ,The white minority in the Caribbean. Princeton NJ: Markus Wiener, 1998. xvi + 179 pp., Karl Watson (eds)-Virginia Heyer Young, Sheryl L. Lutjens, The state, bureaucracy, and the Cuban schools: Power and participation. Boulder CO: Westview Press, 1996. xiii + 239 pp.
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Bivona, Cory, Kevin Li, Priyanka Sharma, Jianghua He, Grace Martin, Andrew K. Godwin, Anthony Rooney, et al. "Abstract P4-10-03: Immunogenicity of SARS-CoV-2 vaccination in subjects on active treatment for breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–10–03—P4–10–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-10-03.
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Abstract Background: Infection with SARS-CoV-2 has led to a global pandemic and has significantly impacted the care of cancer patients. Breast cancer patients receiving active systemic therapy need protection against COVID19 but the efficacy of vaccines in this population is unknown. Although specific biomarkers associated with protection from SARS-CoV-2 infection have yet to be identified, measurement of serum antibody activity is generally accepted as a surrogate of in vivo humoral response to vaccine. This study evaluates the efficiency and durability of binding antibodies to SARS-CoV-2 spike (S) protein in response to COVID19 vaccine in breast cancer patients receiving systemic treatment. Methods: Breast cancer patients, who were unvaccinated, partially or fully vaccinated with Pfizer-BioNTech BNT162b2 (PF), Moderna mRNA-1273 (Mod) or Johnson & Johnson AD26.COV2.S (J&J) were enrolled in this prospective longitudinal study. Eligible patients were on systemic treatment with cytotoxic chemotherapy, chemotherapy plus a checkpoint inhibitor (CPI), CPI alone or a CDK 4/6 inhibitor. Longitudinal blood samples are being collected at baseline, prior to vaccination in unvaccinated patients (T0), 2 weeks after the first vaccine dose and before the second dose for the mRNA vaccines (T1), 1 month (T2), 3 months (T3), 6 months (T4) and 12 month post vaccination. For J&J, there was no T1 timepoint. Roche Elecsys® Anti-SARS-CoV-2 S receptor binding domain (RBD) antibody immunoassay was used to measure antibody titers (range 0.4 to 250 U/mL). Cut points of <0.8 U/mL = negative, ≥0.8 U/mL = seropositive, were based on validated product specifications. Results: Of the 84 breast cancer patients enrolled, 9 had documented COVID infection at baseline and were excluded from analysis. Mean age was 58 years; 99% were female, 85% were Caucasian, 49% had early stage disease and 51% had metastatic breast cancer. 67% were receiving cytotoxic chemotherapy, 20% a CKD 4/6 inhibitor, 13% a CPI with or without chemotherapy. 61.2% were vaccinated with PF, 34.3% with Mod and 4.5% with J&J vaccines. Seropositivity rate for the entire group was 10% at T0, 78% at T1, 98% at T2 and 100% at T3. Seropositivity rates of all cohorts at different timepoints are shown in the table. Mean titers for all patients were 12.6 U/mL at T0, 102.3 U/mL at T1, 204.4 U/mL at T2 and 214.6 U/mL at T3 timepoints. Similar incremental increase in antibody levels was observed in all cohorts (Table). Conclusions: 78% of the patients with breast cancer on active systemic treatment were seropositive after the first dose of COVID19 vaccine and 98% after the second dose. The antibody response was maintained at 3 months, with 100% seropositivity rate. 6-month antibody response will be available at the time of presentation. Durability of antibody response at 6 and 12 months will help determine the timing of additional vaccine booster doses in this population. Importantly, this study has found that active treatment with chemotherapy, immunotherapy or CDK4/6 inhibitor therapy does not impact antibody response to SARS-CoV-2 vaccination in patients with breast cancer. Table: Seropositivity rate and mean Anti-S protein antibody levels by cohort at each time point. T0= baseline, T1=after first vaccine dose (mRNA vaccines), T2= 4 weeks after 2 doses of mRNA vaccine or after single dose of J&J vaccine, T3=3 months after the first dose of vaccine. N% Seropositive (>0.8 U/mL)Mean Antibody Levels (U/mL)T0T1T2T3T0T1T2T3All subjects7510789810012.6102.3204.4214.6Chemotherapy50577961003.3105.6200.0250CDK 4/6 inhibitors15257510010013.786.8234.7205.8CPI + Chemotherapy82583100NA*62.8121.4177.5NA*CPI therapy20100100NA*0.46.82250NA*CPI=Checkpoint Inhibitors; *Timepoint for longitudinal samples not reached Citation Format: Cory Bivona, Kevin Li, Priyanka Sharma, Jianghua He, Grace Martin, Andrew K Godwin, Anthony Rooney, Stephen Williamson, Gary Doolittle, Weijing Sun, Bruce F Kimler, Anne P O'Dea, Lauren E Nye, Joseph P McGuirk, Ziyan Pessetto, Lisa Haney, Nicole Balmaceda, Laura Mitchell, Karissa Finke, Maggie Nelson, Dinesh Pal Mudaranthakam, Natalie Streeter, Stephanie Lafaver, Jaimie Heldstab, Qamar J Khan. Immunogenicity of SARS-CoV-2 vaccination in subjects on active treatment for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-03.
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Isaacs, Claudine, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, et al. "Abstract GS5-03: Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL." Cancer Research 83, no. 5_Supplement (March 1, 2023): GS5–03—GS5–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-gs5-03.
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Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab is an anti-PD-1 inhibitor approved for the treatment of NSCLC and cutaneous basal and squamous cell CA. Lymphocyte activation gene 3 (LAG-3) binds MHC class II leading to inhibition of T-cell proliferation and activation and is often co-expressed with PD-1. REGN3767 is a fully humanized mAb that binds to LAG-3 and blocks inhibitory T-cell signaling. Concurrent blockade of LAG-3 with an anti-PD-1 may enhance efficacy of an anti-PD-1. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included Paclitaxel 80 mg/m2 IV weekly x 12 and Cemiplimab 350 mg and REGN3767 1600 mg both given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. Cemiplimab/REGN3767 was eligible to graduate in 3 of 10 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. The statistical methods for evaluating I-SPY 2 agents has been previously described. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemiplimab/REGN3767 being superior to the dynamic control. Response predictive subtypes (Immune+ vs Immune-) were assessed using pre-treatment gene expression data and the ImPrint signature. Results: 73 HER2- patients (40 HR+ and 33 HR-) received Cemiplimab/REGN3767 treatment. The control group included [357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemiplimab/REGN3767 graduated in both HR-/HER2- and HR+/HER2- groups; estimated pCR rates (as of June 2022) are summarized in the table. Safety events of note for Cemiplimab/REGN3767 include hypothyroidism 30.8%, adrenal insufficiency (AI) 19.2%, hyperthyroidism 14.1%, pneumonitis 1.3%, and hepatitis 3.8%. All were G1/2 except for 6 (7.7%) G3 AI and 3 (3.8%) G3 colitis. Rash occurred in 62.8%, 9% G3 and 2 pts (2.6%) had pulmonary embolism. X% of adrenal insufficiency cases required replacement therapy. 40 patients (11 HR+ and 29 HR-) in Cemiplimab/REGN3767 were predicted Immune+; 32 (29 HR+ and 3 HR-) were predicted Immune-. In the HR+ group pCR was achieved in 10/11 (91%) patients with Immune+ subtype compared with 8/29 (28%) with Immune- subtype. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Dual immune blockade with a LAG-3 inhibitor and anti-PD1 therapy resulted in a high predicted pCR rate both in HR-/HER2- (60%) and HR+/HER2- (37%) disease. The novel Imprint signature identified a group of HR+ patients most likely to benefit from this active regimen. Table 1: Estimated pCR rates Citation Format: Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-03.
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Weiner, Adam C., Marc Williams, Hongyu Shi, Ignacio Vazquez-Garcia, Sohrab Salehi, Nicole Rusk, Sohrab P. Shah, and Andrew McPherson. "Abstract 869: Single-cell DNA replication dynamics in genomically unstable cancers." Cancer Research 84, no. 6_Supplement (March 22, 2024): 869. http://dx.doi.org/10.1158/1538-7445.am2024-869.
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Abstract Background: DNA replication and cell cycle regulation are frequently disrupted as part of a cancer’s progression toward uncontrolled proliferation, generating somatic copy number alterations (CNAs) and producing intratumoral heterogeneity that drives subsequent evolution. Structural variation and CNAs have been shown to impact epigenetic and chromatin states, but our ability to assess their impact on DNA replication timing (RT) and cell proliferation rates remains limited. Single-cell whole genome sequencing (scWGS) is a powerful method for studying clonal heterogeneity and CNAs, and has the potential to provide greater insight into DNA replication dynamics in aneuploid populations. However, computational identification of S-phase cells and distinguishing inherited somatic CNAs from transient DNA replication changes remain challenging. Methods: We present a new method, PERT, which uses a Bayesian framework to model read depth as a combination of somatic copy number, replication, and sequencing bias, enabling estimation of DNA replication profiles and cell cycle phase from scWGS data. Unlike previous approaches, PERT provides unbiased estimates of RT and cell cycle phase which allows for analysis of previously uncharacterized cell types using any scWGS platform. These unique properties enable PERT to perform novel analysis such as estimating clone-specific proliferation rates and studying the interplay between RT and somatic CNAs during tumor evolution. We applied PERT to a cohort of >50,000 scWGS cells obtained from a collection of genomically unstable breast and ovarian cell lines, xenografts and primary cancer tissues. Results: Clone RT profiles correlated with future copy number changes in serially passaged cell lines. Cell type was the strongest determinant of RT heterogeneity, while whole genome doubling (WGD) and mutational signature had weaker RT associations but were associated with accumulation of late S-phase cells. Recurrent CNAs affecting chromosome X had striking impact on RT, with loss of the inactive X allele shifting replication earlier, and loss of inactive Xq resulting in reactivation of Xp. Analysis of time series xenografts illustrated that cell cycle distributions approximate clone proliferation. This relationship enabled us to observe that highly proliferative clones were the most chemosensitive in cisplatin-treated xenografts and, separately, present novel evidence that WGD leads to slower proliferation. Conclusions: Our analysis implicates cell type as the strongest determinant of RT with chrX being the locus of highest RT variation due to X-inactivation. Separately, quantification of S-phase cells enables interrogation of the on- and off-treatment fitness of genetically distinct subclones. This work leads to better understanding of how DNA replication dynamics drive and are further modulated by genomic instability. Citation Format: Adam C. Weiner, Marc Williams, Hongyu Shi, Ignacio Vazquez-Garcia, Sohrab Salehi, Nicole Rusk, Sohrab P. Shah, Andrew McPherson. Single-cell DNA replication dynamics in genomically unstable cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 869.
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Ahmed, Kamran A., Youngchul Kim, Michelle DeJesus, Sasha J. Beyer, Nicole O. Williams, Joshua Palmer, Kristina D. Woodhouse, et al. "Abstract OT2-09-01: Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT2–09–01—OT2–09–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot2-09-01.
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Abstract Background: Breast cancer patients with brain metastases have a high unmet clinical need and improved management strategies are needed. There has been interest in studying CDK 4/6 inhibitors in the management of breast cancer brain metastases. A phase II study has shown abemaciclib to have activity in the management of hormone receptor (HR)+/HER2- brain metastases. Pre-clinical data suggests a potential synergy with CDK inhibitors and radiation therapy. Stereotactic radiosurgery (SRS) is a cornerstone in the management of limited brain metastases. We hypothesize treatment with abemaciclib and SRS will be safe and improve intracranial progression free survival (PFS) compared to abemaciclib alone. Trial Design: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of abemaciclib and endocrine therapy with SRS among patients with HR+/HER2- metastatic breast cancer brain metastases. Treatment will be initiated with one week of abemaciclib followed by stereotactic radiation to sites of brain metastases or post-operative cavities with continued abemaciclib. Safety will be monitored initially by a 3+3 design. If unexpected neurologic toxicities are noted, the dose of radiation therapy will be reduced. This will be followed by a phase II study to evaluate intracranial PFS. Eligibility: Eligible patients include those that are HR+/HER2-, ≥18, ECOG ≤2 with ≤15 breast cancer brain metastases with measurable disease per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Specific Aims: The primary objective of the phase I study is to evaluate the safety and feasibility of abemaciclib and SRS to sites of brain metastases in the management of HR+/HER2- metastatic breast cancer with brain metastases. The primary objective of the phase II portion is to determine PFS intracranially. Secondary objectives include evaluation of extracranial PFS, local and distant intracranial control, and overall survival. Statistical Methods: Safety and feasibility will be monitored in the phase I study using a 3 + 3 design followed by a phase II study to assess intracranial PFS. The phase II study is designed as a single-arm, two-stage trial using the Restricted-Kwak-and-Jung’s method. In the first stage, a total of 21 patients will be enrolled. If pre-specified endpoints are met, an additional 10 patients will be enrolled in the second stage. Patient Accrual: A total of up to 31 patients will be enrolled inclusive of patients in the phase I portion treated at the recommended phase II dose. Clinical trial information: NCT04923542. Citation Format: Kamran A. Ahmed, Youngchul Kim, Michelle DeJesus, Sasha J. Beyer, Nicole O. Williams, Joshua Palmer, Kristina D. Woodhouse, Rashmi K. Murthy, Jing Li, Avan J. Armaghani, John A. Arrington, Ricardo L. Costa, Brian J. Czerniecki, Arnold B. Etame, Peter A. Forsyth, Hung T. Khong, Daniel E. Oliver, Marilin Rosa, Solmaz Sahebjam, Hatem H. Soliman, Aixa E. Soyano, Michael A. Vogelbaum, Michael Yu, Hyo S. Han. Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-09-01.
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LACAZE, Jean Louis, Clémence Brac de la Perrière, Mony Ung, Florence Dalenc, Vincent Nicolai, Eleonore De Maio, Marion Montastruc, et al. "Abstract P1-05-25: Clinical and biological features of 158 consecutive and unselected oligometastatic breast cancers." Cancer Research 83, no. 5_Supplement (March 1, 2023): P1–05–25—P1–05–25. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-05-25.
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Abstract Background: In order to determine the optimal treatment strategy for oligometastatic breast cancer (OMBC), effective and safe treatments for metastatic sites and sensitive and specific imaging techniques are needed. But it is also essential to know the incidence of oligometastatic breast cancer and its clinical and biological characteristics [1]. Efficient imaging techniques and therapeutic tools exist, but knowledge of incidence, clinical and biological characteristics of OMBC is scarce. This is partly due to the lack of publications describing these data on recent, consecutive, and unselected series of OMBC. Methods: we retrospectively collected data from 998 patients diagnosed with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018 at our institution. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis. Hormone receptor (HR) and HER2 receptor status, histology, SBR grade, number of metastases and organs affected were collected. Results: Of 998 MBC, 15.8% were OMBC (158/998). Among the series, 88% (139/158) of OMBC had 1 to 3 metastases and 86.7% (137/158) had only one organ involved. Among 158 patients, 52.5% (n=83) had bone metastases, 20.9% (n=33) had lymph node metastases, 14.6% (n=23) had liver metastases, 13.3% (n=21) had brain metastases, 8.2% (n=13) had lung metastases, and 3.8% (n=6) had others (skin, pancreas, adrenal). Among these 158 patients, 83.4% (n=131) had ductal breast carcinoma, 55.7% (n=88) had HR+/HER2- OMBC, 25.3% (n=40) had HER2+ OMBC and 19% (n=30) had HR-/HER2- OMBC. HR+/HER2- subtype was statistically associated with bone and bone only metastases (p=0.001), HER2+ subtype with brain metastases (p=0.001) and HR-/HER2- subtype with lymph node metastases (p=0.008). Visceral metastases (lung or liver) are not statistically associated with any biological subtypes. The proportion of OMBC with SBR grade III was statistically higher than in a series of 22,109 patients with MBC [2] (49.4% vs 35.2%; p< 0.001). Conclusion: OMBC is a heterogeneous entity. OMBC incidence is certainly much higher than the commonly used values. OMBC is not an indolent disease, and each subgroup, according to its biological and anatomical characteristics, may deserve a specific management. [1] Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol Off J Am Soc Clin Oncol 1995;13:8–10. https://doi.org/10.1200/JCO.1995.13.1.8. [2] Deluche E, Antoine A, Bachelot T, Lardy-Cleaud A, Dieras V, Brain E, et al. Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008–2016. Eur J Cancer 2020;129:60–70. https://doi.org/10.1016/j.ejca.2020.01.016. Citation Format: Jean Louis LACAZE, Clémence Brac de la Perrière, Mony Ung, Florence Dalenc, Vincent Nicolai, Eleonore De Maio, Marion Montastruc, Bastien Cabarrou, Nils Monselet, Ciprian Chira, Gauthier Glemarec, Thibaut Cassou-Mounat. Clinical and biological features of 158 consecutive and unselected oligometastatic breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-25.
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Zimmer, Alexandra S., Seth Steinberg, Mark Gilbert, Terri Armstrong, Eric Burton, Nicole Houston, Dee Dee Smart, et al. "Abstract P1-21-06: Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–21–06—P1–21–06. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-21-06.
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Abstract Background: The incidence of breast cancer brain metastases is rising, and, these lesions in the central nervous system (CNS) and their treatments cause physical and neurocognitive impairment. Only modest incremental advances in progression free survival have been achieved with drugs to treat CNS lesions, while nearly half of the patients who receive SRS will develop new brain metastases within 1 year. In murine models of breast cancer, we demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion significantly prevented development of brain metastases. No effect, however, was seen in established brain metastases or systemic breast cancer metastases. We hypothesize that low dose, metronomic TMZ will prevent the outgrowth of brain lesions in HER2+ patients, when added to an active anti-HER2 treatment. We present here the results of the phase I trial combining T-DM1 to TMZ for the prevention of additional brain metastases after their first occurrence and local treatment. Methods: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of local brain metastases therapy (WBRT, SRS and or surgery), with PS 0-2 and adequate end organ function. Standard doses of T-DM1 were administered IV every 21 days (3.6 mg/kg) and TMZ was given PO daily in a 3+3 design at 30, 40 or 50 mg/m2, continuously. The DLT period was one 21d cycle. Safety was assessed by CTCAEv4.0 and response by RECISTv1.1 and RANO-BM. Brain MRI and systemic CT scans were performed every 6 weeks. Blood samples for correlatives evaluation were collected at baseline and every cycle while on trial. CSF was collected at baseline and C3D1 for all patients. Questionnaires (MDASI-BT and PROMIS®) for evaluation of symptoms and quality of life were completed every 6 weeks. Results: Twelve women with median age 55.5yr (44-67) were enrolled. Only 3 (25%) patients had HR+/HER2+ tumors at initial diagnosis. Nine (75%) patients presented stages II and III disease at initial diagnosis, and developed brain metastases at the diagnosis of first recurrence. Nine (75%) patients received SRS therapy and 3 (25%) received WBRT prior to trial enrollment. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12) and decreased CD4 (6/12), requiring pentamidine for PCP prophylaxis. No DLT was observed. Four patients underwent dose reductions (thrombocytopenia, fatigue and peripheral neuropathy), all of them enrolled on the highest TMZ dose. Median follow-up on study is now 9.6m (1.2-32) and no patient developed new parenchymal brain metastases. Five patients remain on study, while 7 are off study due to progression at previously irradiated CNS lesion (2), progression of systemic disease (2), focal leptomeningeal involvement (1), new cancer (1) and persistent thrombocytopenia (1). Completion rates for the questionnaires were 99% by Cycle 15 (81 completed out of expected 82) and 90% by Cycle 41 (123/137), and will be reported at presentation. Conclusion: Metronomic TMZ in combination with standard dose T-DM1 is tolerable and shows promising activity in secondary prevention of HER2+ brain metastases. Systematic longitudinal symptom assessments in breast cancer patients with brain metastasis are feasible. A randomized phase II expansion of this trial with T-DM1 or T-Dxd +/- TMZ is planned. Citation Format: Alexandra S Zimmer, Seth Steinberg, Mark Gilbert, Terri Armstrong, Eric Burton, Nicole Houston, Dee Dee Smart, Nadia Biassou, John Butman, Priscilla K Brastianos, Carey K Anders, Stanley Lipkowitz, Patricia S Steeg. Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-06.
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Sissi, Claudia, Marta Cozzaglio, Riccardo Rigo, Nicolo Dal Ponte, Martina Rotondo, Silvia Ceschi, Barbara BIondi, and Barbara Spolaore. "Abstract LB036: Back and forth from structure to functional target: The interplay between Vimentin and non-canonical nucleic acid arrangements." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB036. http://dx.doi.org/10.1158/1538-7445.am2024-lb036.
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Abstract Vimentin, a member of type III intermediate filaments (IFs), is a cytoskeletal protein that covers multiple architectural and functional roles, including the maintenance of organelle positioning in the cytoplasm, the regulation of cytoskeletal rearrangements, while more recently its potential involvement as a regulatory factor in gene expression emerged. Additionally, it is involved in cell migration and epithelial-to-mesenchymal transition (EMT). In previous works, we identified Vimentin as the first known protein that selectively binds G-quadruplexes repeats (G4-repeats). This DNA folding consists of repeated units of nucleic acid sequences arranged into G-quadruplex (G4s). Their three-dimensional features largely differ from the most common single-stranded or double-helix nucleic acids as well as from the isolated G4 modules. Noteworthy, they occur at a small subset of genomic sites, associated with cell proliferation and migration, where they can recruit the soluble nuclear pool of Vimentin. Altogether, this information led us to consider the Vimentin-DNA complex as a promising target for developing small molecule binders capable of inhibiting cell migration and, eventually, EMT. To properly set up a rational drug-design approach, we integrated different advanced biophysical tools (Hydrogen-Deuterium Exchange, Cryo-Electron Microscopy) to derive a comprehensive picture of the protein-DNA complex at the molecular level. This approach allowed us to map the interaction surface between the soluble tetrameric form of Vimentin and a G4-repeat. Based on this data, we initiated a screening campaign using focused libraries of small molecules and peptides, which were rationally designed according to the structural features of the Vimentin-G4-repeats complex. The capability of the identified hits to prevent the recognition of the nucleic acid by Vimentin has been investigated This approach allowed us to identify attractive novel entities that prevent the Vimentin-G4-repeat complex formation according to different molecular mechanisms. These systems are now under further refinement moving from the test tube to the cellular environment, where the dynamic behavior of these nucleic acid domains as well as the recruitment of different proteins by Vimentin might alter the architectural features of the target. References: Ceschi S, Berselli M, Cozzaglio M, Giantin M, Toppo S, Spolaore B, Sissi C (2022) Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters Nucleic Acid Res, 50(3):1370-1381 Buglione E, Salerno D, Marrano CA, Cassina V, Vesco G, Nardo L, Dacasto M, Rigo R, Sissi C, Mantegazza F (2021) Nanomechanics of G-quadruplexes within the promoter of the c-kit oncogene. Nucleic Acid Res, 49, 4564-4573 Citation Format: Claudia Sissi, Marta Cozzaglio, Riccardo Rigo, Nicolo Dal Ponte, Martina Rotondo, Silvia Ceschi, Barbara BIondi, Barbara Spolaore. Back and forth from structure to functional target: The interplay between Vimentin and non-canonical nucleic acid arrangements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB036.
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Darlix, Amélie, Stéphane Pouderoux, Simon Thezenas, Alexis Bievelez, William Jacot, Laure Cayrefourcq, Nicolas Menjot-de-Champfleur, Cristina Leaha, and Catherine Alix-Panabières. "Abstract P2-01-12: Detection of circulating tumor cells in cerebrospinal fluid for patients with suspected breast cancer leptomeningeal metastases: A prospective study." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–01–12—P2–01–12. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-01-12.
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Abstract Background Breast cancer (BC) is the most frequent cause of leptomeningeal metastases (LM). LM diagnosis is confirmed by the detection of tumor cells in the cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, even with optimal CSF sample volume and time to the analysis, the sensitivity of this technique is low, demanding repeated samples. Here, we aimed to evaluate the value of circulating tumor cell (CTC) detection in CSF using the CellSearch® system for LM diagnosis. Materials and Methods This prospective, monocentric study included adult BC patients with suspected LM (clinical and/or radiological signs). CSF samples from 1-3 lumbar puncture(s) were analyzed: protein level, conventional cytology (60 drops), and CTC detection with the CellSearch® system (60 drops, first lumbar puncture only). Sensitivity (Se) and specificity (Sp) were calculated, using the results of the conventional cytology as the gold-standard. Results Forty-nine eligible patients were included (Jan 2017-Jan 2020): median age 51.8, 95.9% women, 20.4% HER2+ BC, 93.8% previously diagnosed with metastatic BC, 89.8% with clinical symptoms. Among them, 40 were evaluable (CTC detection failure: n=8, eligibility criteria failure: n=1). Median sample volume was 3.0 mL for conventional cytology samples (median time to analysis: 22min) and 3.3 mL for CTC samples. Of the 40 evaluable patients, 18 had a positive cytology (on CSF sample n=°1/n°2: n=16/n=2) and were therefore diagnosed with LM using the gold-standard method. Protein level was elevated in 88.2% of these patients, compared with 45.1% of patients with negative CSF cytology (p=0.005). CTCs were detected in these 18 patients (median 5824 CTCs, range 93-45052). CTCs were also detected in 5/22 patients with a negative cytology (median 2 CTCs, range 1-44). Among them, one patient (44 CTCs) was diagnosed with a cytologically-proven LM 9 months later, while there was no further argument for LM in the other 4 patients’ history (1-3 CTC), who died of the extra-cerebral disease after a median time of 5.2 months (range 0.9-25.9). The detection of at least one CTC in CSF was associated with a Se of 100.0% (IC95% 82.4-100) and a Spe of 77.3% (IC95% 64.3-90.3) for the diagnosis of LM. Considering the number of CTC as a quantitative value, we determined the cut-off maximizing the Youden index using the ROC analysis (93 CTC). The detection of at least 93 CTC in CSF was associated with a Se and a Spe of 100.0% for the diagnosis of LM (area under the curve [AUC]: 1.0). Conclusion CTCs were detected with the CellSearch® system in all patients diagnosed with a cytologically-proven LM, as well as in a few patients without a cytological confirmation of LM. The prognosis of these patients with CSF cytology-/CTCs+ needs to be further investigated in a larger cohort. Citation Format: Amélie Darlix, Stéphane Pouderoux, Simon Thezenas, Alexis Bievelez, William Jacot, Laure Cayrefourcq, Nicolas Menjot-de-Champfleur, Cristina Leaha, Catherine Alix-Panabières. Detection of circulating tumor cells in cerebrospinal fluid for patients with suspected breast cancer leptomeningeal metastases: A prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-12.
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Yang, Lin, Qinggang Wang, Jessica McNeil, Charles Matthews, Leanne Dickau, Jeff Vallance, Margaret McNeely, et al. "Abstract PS02-04: Associations of sleep health with quality of life among women with newly diagnosed breast cancer: baseline results from the AMBER cohort study." Cancer Research 84, no. 9_Supplement (May 2, 2024): PS02–04—PS02–04. http://dx.doi.org/10.1158/1538-7445.sabcs23-ps02-04.
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Abstract Background High incidence, ageing, and advancements in early detection and clinical treatment have led to a growing breast cancer survivor population, particularly in developed countries. Sleep problems are common and persist in this population, affecting over 50% of breast cancer survivors. Good sleep health is characterized by sleep duration, sleep timing and sleep quality, and these three dimensions do not necessarily correlate with each other. This analysis aimed to investigate the associations of sleep health, characterized by sleep duration, sleep timing, and a range of metrics for sleep quality (latency, efficient, disturbance, medication, daytime dysfunction) with physical and mental well-being in women with newly diagnosed breast cancer. Methods Newly diagnosed breast cancer patients, with early-stage disease were recruited between 2012-2019 in Edmonton and Calgary, Canada, and completed the Pittsburg Sleep Quality Index (PSQI) to assess the habitual sleep duration and timing, as well as sleep latency, efficiency, disturbance, medication and daytime dysfunction. To measure quality of life, participants completed the SF-36 version-2 to assess their physical and mental well-being. Multivariable linear regressions were used to estimate the association of sleep characteristics with physical and mental well-being, adjusting for socio-demographic, disease, clinical and lifestyle behaviour factors. Results Among 1409 breast cancer survivors, 41% reported short or long sleep duration ( < 6 or ≥9 h/d), 41% reported habitual bedtimes after 11pm, 56% reported sleep efficiency being < 85%, 80% reported fairly good (vs. very good) sleep disturbance, 35% reported taking sleep medication in the past month, and 71% reported fairly good, fairly bad or very bad (vs. very good) daytime function. In the multivariable model, short sleep (≤6/d) was associated with worse mental well-being (-3.6, 95%CI: -4.7,-2.4) but not physical well-being (-1.5, 95%CI: -2.3,-0.7). No clinically meaningful differences in quality of life were found for sleep timing. Metrics characterizing suboptimal sleep quality were associated with poorer physical and mental well-being, with stronger associations observed for mental health well-being. Notably, only 20% and 29% women were classified as “very good” in sleep disturbance and daytime dysfunction measures, respectively. Nevertheless, even “fairly good” sleep disturbance and daytime dysfunction were associated with statistically and clinically meaningful significant poorer physical (-3, 95%CI: -3.8,-2.2) and mental (-8, 95%CI: -9,-7) well-being. Conclusion Sleep timing does not appear to affect the quality of life in a clinically meaningful manner in women newly diagnosed with breast cancer. In contrast, short sleep duration and worse sleep quality were strongly associated with poorer mental well-being in these women. Targeted interventions to improve sleep may lead to improvements in the quality of life among women with newly diagnosed breast cancer. Table 1. Association of Sleep Characteristics with SF-36 Measured Quality of Life, Physical Well-Being. Table 2. Association of Sleep Characteristics with SF-36 Measured Quality of Life, Mental Well-Being. Citation Format: Lin Yang, Qinggang Wang, Jessica McNeil, Charles Matthews, Leanne Dickau, Jeff Vallance, Margaret McNeely, S. Nicole Culos-Reed, Karen Kopciuk, Kerry Courneya, Christine Friedenreich. Associations of sleep health with quality of life among women with newly diagnosed breast cancer: baseline results from the AMBER cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-04.
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Pontolillo, Letizia, Carolina Reduzzi, Andrew A. Davis, Arielle J. Medford, Annika Putur, Lorenzo Gerratana, Katherine Clifton, et al. "Abstract 977: Germline BRCA1/2 mutations detected by circulating tumor DNA testing in breast cancer patients: A retrospective mutiinstitutional analysis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 977. http://dx.doi.org/10.1158/1538-7445.am2024-977.
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Abstract Background: The use of circulating tumor (ct) DNA testing allows to detect resistant and actionable somatic alterations and it could be associated with the incidental identification of germline mutations. An univocal variant allele frequency (VAF) threshold to distinguish germinal form somatic mutations has not been assessed yet. We aimed to correlate BRCA1/2 ctdNA detected mutations with germline mutational status to determine potential VAF cutoff. Materials and methods:We retrospectively analyzed the incidence of both somatic (s) and germinal (g) BRCA1/2 alterations in a multiinstitutional retrospective breast cancer (BC) cohort to assess the VAF threshold for the likelihood of germline mutations’ detection by ctDNA next-generation sequencing (Guardant 360) testing. Clinical variables were analyzed using descriptive analyses and receiving operating characteristic (ROC) curves were generated to determine the VAF cutoff. Results: Two hundred and fourteen patients (pts) with sBRCA1/2 mutations (including variant of uncertain significant and synonymous) detected by ctDNA testing, referred to the enrolling centers between January 2015 to May 2023 were included in the analysis. The median age at diagnosis was 50 years old (Interquartile range (IQR)43,5-61.5), 43% had a family history of cancer. Hormone receptor positive/HER2 negative was the most represented subtype (68%) followed by the HER2 positive (16%) and triple negative (16%) ones. At ctDNA baseline, 95.8% of pts had a metastatic disease; the main sites of metastases were bone (67.4%) and visceral (59.3%). Ninetyfour (43.9%) and 137 (64%) pts had a sBRCA1 and sBRCA2 alterations respectively, while 17 (7.9%) had a co-mutation in BRCA1 and BRCA2. The mean VAF value for sBRCA1 alterations was 10.1% (standard deviation (SD) 19.5%, range [0.04%-84.3%]) while for sBRCA2 alterations was 10.8% (SD 18.9%, range [0.21%-80.3%]). The germinal testing, performed per standard of care, was available for 100 pts (46.7%). Among these, 42 (42%) had at least a pathogenic variant detected. A gBRCA1 mutation was present in 11 (11%) pts while 25 (25%) had a gBRCA2 mutation. Comparing the somatic and germinal testing, 9/100 pts had a concordance for BRCA1 detection, the 2 discordant cases had both a low allele frequency sBRCA2 alterations; the concordance for BRCA2 detection was instead 100%. An optimal cutoff of 38.4% (AUC 0.98) for BRCA1 and 19.5% (AUC 0.96) for BRCA2 was assessed by ROC analysis as the likelihood of a germline meaning of a somatic mutation detected by ctDNA analysis. Conclusion: The identification of BRCA1/2 alterations in ctDNA could guide the use of germline testing. The VAF cutoff identified for the likelihood of a germinal mutation is lower than expected, suggesting that a wider population should be screened for germinal mutation with relevant impact on the therapeutic choices and family screening. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew A. Davis, Arielle J. Medford, Annika Putur, Lorenzo Gerratana, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Surbhi Warrior, Mara S. Serafini, Eleonora Nicolò, Laura Munoz-Arcos, Jeannine Donahue, Charles S. Dai, Jennifer C. Keenan, Amir Behdad, William J. Gradishar, Diana Giannarelli, Emilio Bria, Cynthia X. Ma, Aditya Bardia, Massimo Cristofanilli. Germline BRCA1/2 mutations detected by circulating tumor DNA testing in breast cancer patients: A retrospective mutiinstitutional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 977.
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Altman, Julia E., Carson J. Walker, Emily K. Zboril, Nicole S. Hairr, Rachel K. Myrick, David C. Boyd, Jennifer E. Koblenski, et al. "Abstract 1750: Decoding breast cancer: Unraveling subtype and model differences through multi-model single-cell RNA sequencing data integration." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1750. http://dx.doi.org/10.1158/1538-7445.am2024-1750.
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Abstract Breast cancer's complex transcriptional landscape requires a deep understanding of sample and cell diversity to identify effective treatments. In this study, we amalgamate single-cell RNA sequencing data from breast cancer patient-derived xenografts (PDX), organoids, cell lines, patient tumors and reduction mammoplasties resulting in a comprehensive dataset of 117 samples with 506,719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 enriched (HER2E), and triple-negative breast cancer (TNBC) subtypes. We aimed to delineate similarities and distinctions across model systems and patient samples while also exploring stratification of therapeutic drug efficacy based on subtype proportions within tumors. Mammary tumor PDXs, organoids, and established cell lines exhibited higher proliferation and lower heterogeneity observed via UMAP dimensionality reduction compared to most patient tumors or normal breast epithelium. TNBCs had elevated proliferative and pro-metastatic signatures compared to HR+ and HER2E samples. Interestingly, compared to matched PDX tumors, organoids from these same models were found to exhibit stark differences in gene expression, including upregulation of metabolically active aldo-keto reductase family genes, highlighting differences in the model systems with implications for pre-clinical drug testing. Single-cell tumor subtyping analyses with scSubtype and TNBCtype methods found that therapeutically treated samples had shifts in the proportions of cell-wise subtype annotations when compared to matched untreated samples. Similarly, patient lymph node metastasis when compared with matched primary tumors were significantly linked to decreases in Basal-like and HER2-enriched cell-wise annotations in untreated ER+ samples. In vitro assessment of anti-cancer compounds on PDX cells showed significant correlation of subtype proportion with cell viability following treatment with targeted therapeutic agents. This subtyping methodology offers a powerful tool to monitor the evolving gene expression landscape within samples and predict responses to therapeutic agents. We present here a dynamic approach to cell-wise sample annotation and a substantial multi-model dataset for use facilitating informed decision-making in preclinical research and therapeutic development. Citation Format: Julia E. Altman, Carson J. Walker, Emily K. Zboril, Nicole S. Hairr, Rachel K. Myrick, David C. Boyd, Jennifer E. Koblenski, Madhavi Puchalapalli, Bin Hu, Mikhail G. Dozmorov, Xi Chen, Yunshun Chen, Charles M. Perou, Brian D. Lehmann, Jane E. Visvader, Amy L. Olex, J. Chuck Harrell. Decoding breast cancer: Unraveling subtype and model differences through multi-model single-cell RNA sequencing data integration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1750.
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Barnabas, Georgina D., Tariq A. Bhat, Verena Goebeler, Pascal Leclair, Nadine Azzam, Nicole Melong, Jason N. Berman, et al. "Abstract 937: Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe." Cancer Research 84, no. 6_Supplement (March 22, 2024): 937. http://dx.doi.org/10.1158/1538-7445.am2024-937.
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Abstract Translation of precision oncology data into feasible precision therapies for hard-to-cure childhood, adolescent and young adult malignancies remains a significant challenge. Identifying therapeutic targets at the protein and pathway level and demonstrating treatment response in personalized models hold great promise, particularly for combination therapies, but may be considered complex and time consuming. Here, we present the case of an adolescent with metastatic, progressive spindle epithelial tumor with thymus-like differentiation (SETTLE) and evaluate how proteomics combined with rapid patient-derived models can identify treatment options not apparent at the genome or transcript level. Mass spectrometric proteome analysis of macro-dissected tumor and adjacent normal from formalin fixed paraffin embedded sections was completed within two weeks of biopsy and identified key proteins involved in one-carbon metabolism, including SHMT2 and DHFR as possible targets for single or combination therapy. Elevated SHMT2 levels were validated by immunohistochemistry and compared to levels across AYA tumors. Based on the suitability for an innovative therapy trial, we prioritized single-agent sertraline, a commercially available anti-depressant medication that inhibits SHMT2, and confirmed a positive drug response in both chicken chorioallantoic membrane (CAM) and larval zebrafish xenografts generated from the patient. Retrospective expansion in a murine xenograft enabled metabolic tracing on isolated SETTLE- patient-derived xenograft cells using 13C6-glucose confirming SHMT2 activity and response to in vitro treatment. Following failure of cytotoxic chemotherapy and second-line sorafenib treatment, a monotherapy trial of sertraline was initiated by the patient but stopped after 8 weeks after evidence of progressive disease. Possible combination therapies were evaluated further in the patient-derived models. Combining sertraline with the common antibiotic trimethoprim, resulted in enhanced growth inhibition of SETTLE cells in the larval zebrafish xenografts. Significance: Overall, we demonstrate that proteomics and personalized xenograft models may provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact clinical practice. Citation Format: Georgina D. Barnabas, Tariq A. Bhat, Verena Goebeler, Pascal Leclair, Nadine Azzam, Nicole Melong, Jason N. Berman, Jennifer A. Chan, Donna L. Senger, Seth Parker, Christopher A. Maxwell, Gregor S. Reid, Jonathan Bush, Caron Strahlendorf, Rebecca Deyell, C James Lim, Philipp F. Lange. Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 937.
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Morello, Aurore, Mylène Deramé, Marion Drouin, Emmanuelle Wilhelm, Stéphanie Neyton, Irène Baccelli, Caroline Mary, et al. "Abstract 6342: Anti-tumor in vivo efficacy of different classes of anti-CLEC-1 myeloid checkpoint antibodies in monotherapy and in combination with chemotherapeutic agents." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6342. http://dx.doi.org/10.1158/1538-7445.am2024-6342.
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Abstract The c-type lectin receptor CLEC-1 is a pattern recognition receptor [1] expressed by endothelial and myeloid cells in mice, non-human primates, and humans. While genetic deletion of CLEC-1 in mice does not lead to any developmental defect, CLEC-1 deletion or CLEC-1 targeting promotes anti-tumor response by increasing cross-presentation of necrotic or damaged cells by cDC1 dendritic cells and by enhancing T-cell activation [2]. To date, the identification of CLEC-1 endogenous ligand(s) and their biological activity into myeloid or endothelial cells remained to be fully investigated. We aimed to further characterize ligands that are involved into CLEC-1 activation and develop monoclonal antagonist anti CLEC-1 antibody anti-tumor therapy that are able fully counteract inhibitory signaling induced into myeloid cells. Using LC/MS campaign, we confirmed CLEC-1 specific binding to the E3 ubiquitin ligase TRIM21and to the secreted histidine rich glycoprotein (HRG) as previously described [2] and also identify several novel intra-cellular and cell surface proteins that bind to CLEC-1 receptor in protein specific-manner. To block interaction of CLEC-1 ligands, we developed different class of antagonist monoclonal antibodies and evaluated their anti-tumor efficacy in humanized CLEC-1 KI orthotopic and ectopic tumor mouse models fully resistant or partially resistant to ICI therapy. While blocking of CLEC-1 binding to its secreted ligand HRG moderately increases anti-tumor responses, inhibition of CLEC-1 binding to its cytoplasmic and membrane ligands significantly impairs MC38 tumor growth (n=12, p=0.04). Importantly, high anti-tumor efficacy was observed in combination therapy with cyclophosphamide in MC38 mouse model. Additionally, antagonist anti-CLEC-1 antibodies significantly increase overall survival of Hepa1.6-bearing mice (n=32 for each treatment, p<0.002), as compared to corresponding isotype control treatment in 3 independent experiments. Altogether, our results further dissect the mechanism of action of the myeloid checkpoint CLEC-1 in its ability to impair anti-tumor immunity and support its use as a novel and highly promising anti-CLEC antagonist antibody for cancer immunotherapy. Citation Format: Aurore Morello, Mylène Deramé, Marion Drouin, Emmanuelle Wilhelm, Stéphanie Neyton, Irène Baccelli, Caroline Mary, Vanessa Gauttier, Isabelle Girault, Kévin Biteau, Cécile Batty, Géraldine Teppaz, Ariane Desselle, Marion Colonello, Marine Malloci, Elise Chiffoleau, Nicolas Poirier. Anti-tumor in vivo efficacy of different classes of anti-CLEC-1 myeloid checkpoint antibodies in monotherapy and in combination with chemotherapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6342.
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Ganapathi, Shireen S., Emma Wrenn, Nicolas Garcia, Neerja Katiyar, Aya Miyaki, Yuqi Kang, Marina Chan, Taran S. Gujral, and Elizabeth R. Lawlor. "Abstract 150: Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase." Cancer Research 84, no. 6_Supplement (March 22, 2024): 150. http://dx.doi.org/10.1158/1538-7445.am2024-150.
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Abstract Outcomes for patients with recurrent and metastatic Ewing sarcoma (EwS) are dismal and novel therapies are needed. As EwS are initiated and maintained by the EWS::FLI1 transcription factor, agents that target aberrant gene transcription are of interest and bromodomain inhibitors (BETi) have shown promise in preclinical models. Nevertheless, despite initial efficacy, BETi tolerance emerges across tumor types, often via transcriptional rewiring. We reasoned that the therapeutic potential of BETi in EwS could be augmented by identifying and targeting mechanisms of drug resistance. To investigate this, we performed transcriptional and phenotypic profiling of BETi-naïve, responsive, and drug-tolerant (DT) EwS cells and used these data to nominate biologically-informed drug combinations. EwS cells (A673, CHLA10, TC32) were exposed for 72 hrs or 20 days to BMS-986158, a clinical grade BETi being tested in a phase I pediatric clinical trial (NCT0393465). A profound cytostatic effect was observed at 72 hrs but in all cell lines proliferation was restored by 20 days. RNA-seq confirmed reversion of the EWS::FLI1-dependent gene signature at 72 hrs and this was maintained at 20 days, demonstrating continued on-target effects despite restored growth of DT cells. Interrogation of differentially expressed genes between drug naïve, cytostatic, and DT cells indicated that that DT cells had been transcriptionally rewired to more mesenchymal states, with notable upregulation of genes involved in integrin signaling. In support of this, DT populations displayed more fibroblastic morphologies, increased F-actin filaments, and enhanced invasion in collagen-rich 3D culture. In parallel, an unbiased kinase inhibitor screen that exploits mathematical modeling revealed that, while BETi-treated cells were overall more resistant than parent cells to kinase inhibitors, their viability depended on focal adhesion kinase (FAK) activity. Western blot confirmed increased phospho-FAK in DT cells. We next tested BMS-986158 and the FAK-inhibitor Defactinib singly or in combination in vitro and in vivo. Defactinib induced cell death in 2D cultures and blocked invasion of 3D spheroids in collagen. Conversely, BMS-986158 enhanced invasive potential in 3D. The combination of Defactinib and BMS-986158 in naïve and DT populations was highly synergistic in 2D assays. In 3D collagen assays, viability and invasion of DT tumor spheroids were significantly reduced by the combination. Finally, ongoing studies show that the combination of FAK and BET inhibition prolongs survival of mice with EwS tumor xenografts. Thus, our studies reveal that exposure of EwS cells to BETi induces transcriptional rewiring that activates integrin and FAK signaling, restoring proliferation. This work supports further investigation of FAKi as agents that could prevent or reverse the BETi tolerant state in EwS. Citation Format: Shireen S. Ganapathi, Emma Wrenn, Nicolas Garcia, Neerja Katiyar, Aya Miyaki, Yuqi Kang, Marina Chan, Taran S. Gujral, Elizabeth R. Lawlor. Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 150.
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Hum, Nicholas R., John M. Rolison, Nicole F. Leon, Ali Navid, Aimy Sebastian, Josh Wimpenny, and Gabriela Loots. "Abstract 6850: Unraveling molecular factors contributing to metallomic dyshomeostasis induced by triple-negative breast cancer using single-cell RNA sequencing." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6850. http://dx.doi.org/10.1158/1538-7445.am2024-6850.
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Abstract Triple-negative breast cancer (TNBC) comprises 20% of breast cancer cases and exhibits an aggressive phenotype with increased metastasis; these patients have limited treatment options, poorer prognosis and higher mortality than other breast cancers (BC). Metallomics is a relatively new discipline that studies the abundance of metal ions in biological samples. Metallomic analysis has identified differences in BC patients in elements such as iron (Fe) and zinc (Zn) but it is unclear if these reflect metabolic changes in the tumor. In this study, we conducted metallomic profiling to characterize 55 trace elements in the circulation and in the tumor microenvironment of orthotopic mammary fat pad tumors from two isogenic BC cell lines (highly metastatic 4T1; nonmetastatic 67NR). We complemented this analysis with single-cell RNA sequencing of the tumor to determine if complementary changes occur in molecules known to utilize metals as co-factors or transporters and identify drivers of metal metabolism in different tumors. We performed analysis on systemic metal elements by examining whole blood (including blood cells and platelets) and plasma separately. Tumor samples were assessed at the whole tissue level, and we also profiled separated immune or non-immune cells from the tumor. Li, Na, Mg, P, S, K, Ca, Fe, Cu, Zn, Rb were detectable within 100ul of input of whole blood or plasma. Metallomic analysis of the tumor and associated cell populations detected differential levels of Na, Mg, P, S, K Ca, Fe, Zn, and Rb from an average of 200mg of tissue or 2 million cells. Based on scRNAseq analysis, 67NR tumors were composed of greater proportions of cancer cells relative to the 4T1 tumors (79.1% vs 58.8% of tumor cells respectively) and endothelial cells (2.5% vs 1.8%). 4T1 tumors contained an increased abundance of cancer-associated fibroblasts (5.6% vs 2.1%) as well as immune infiltration (33.8% vs 16.3%). Fibroblasts and macrophage populations also showed elevated metal transporter expression levels based on gene expression relative to other tumor residing cell types yet minor differences induced by cancer type. Cancer cells express high levels of metal transport genes (Zn, Ca, Co, Na, Mg, Fe). 67NR cancer cells exhibited increased gene expression of many metal-transporting proteins including numerous solute carrier (SLC) group of membrane transport proteins such as Slc41a2 when compared to the more aggressive 4T1 cells. This study underscores the potential of linking metallomic profiling to tumor composition and cancer behaviors, offering a pathway for identifying novel biomarkers to differentiate aggressive and non-aggressive forms of breast cancer. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. Citation Format: Nicholas R. Hum, John M. Rolison, Nicole F. Leon, Ali Navid, Aimy Sebastian, Josh Wimpenny, Gabriela Loots. Unraveling molecular factors contributing to metallomic dyshomeostasis induced by triple-negative breast cancer using single-cell RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6850.
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Carnazza, Michelle, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Humayun K. Islam, Julie S. Di Martino, Raj K. Tiwari, and Jan Geliebter. "Abstract 5663: Collagen COL26A1 correlates with poor papillary thyroid cancer prognosis and in vitro characteristics of metastasis indicating a potential role as a biomarker or therapeutic target." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5663. http://dx.doi.org/10.1158/1538-7445.am2024-5663.
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Abstract Papillary thyroid cancer (PTC) is the most common cancer in young women and is increasing 3% annually in incidence. While PTC is often slow-growing and surgically resectable, recurrence years to decades later occurs in 20% of patients (now only in their 40s/50s), decreasing survival by ~60%. The identification of prognostic biomarkers and actionable therapeutic targets for high-risk PTC is critically important and an unmet need. RNASeq analysis of our repository of PTC and matched normal tissues identified collagen 26A1 (COL26A1) as significantly upregulated in patients with extrathyroidal extension (ETE), lymph node metastasis, and multifocal tumors, indicative of high-risk for recurrence. Correspondingly, survival curves of The Cancer Genome Atlas (TCGA) demonstrated increased COL26A1 expression decreases survival probability by 25% (p=0.0086) and correlated with MACIS score (q=0.001), differentiation score (q=0.025), tumor stage (q=0.025), and ETE (p=0.0038). COL26A1 expression was increased in PTC cell lines K1 (3-fold) and TPC1 (5-fold) compared to “normal” thyroid epithelial cells, NThy-ori-3-1. CRISPR knockdown of COL26A1 repressed RNA (50%) and protein (70%) expression. COL26A1 repression decreased known cancer-promoting activities of collagens, including proliferation (30%), clonogenicity (33%), anchorage-independent growth (37%), cell motility (43%), Matrigel invasion (30%), in situ gelatin degradation (70%), and migration (33%). Cell-to-cell adhesion and cell-matrix adhesion also decreased (36% and 25%, respectively). This coincided with reduced anoikis resistance (31%), increased MMP expression (50%), and reductions in mesenchymal markers (30%) and increases in epithelial markers (3-fold). Evidence that COL26A1 is a secreted protein was validated by conditioned media isolations whereby expression was decreased in knockdowns compared to control cells (70%). Preliminary data indicate the control cells’ conditioned media can restore the aggressive phenotypes, including cell motility (51%). Qiagen Ingenuity Pathway Analysis (IPA) elucidated the potential role of androgen receptor (AR) in linking COL26A1 with PTC, coinciding with the known effects of sex hormones on collagen expression and organization, and the sex disparity in PTC. Preliminary data indicate that physiologic levels of androgen decrease COL26A1 RNA (46%) and protein (45%) expression in K1 cells expressing the androgen receptor. Thus, COL26A1 may serve as a prognostic marker and actionable target for small molecule inhibitors in high-risk PTC. Citation Format: Michelle Carnazza, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Humayun K. Islam, Julie S. Di Martino, Raj K. Tiwari, Jan Geliebter. Collagen COL26A1 correlates with poor papillary thyroid cancer prognosis and in vitro characteristics of metastasis indicating a potential role as a biomarker or therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5663.
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Walker, Carson J., Julia E. Altman, Emily K. Zboril, Rachel K. Myrick, Nicole S. Hairr, David C. Boyd, Bin Hu, Mikhail G. Dozmorov, and J. Chuck Harrell. "Abstract 1986: Acquisition of carboplatin resistance corresponds with reduced sacituzumab govitecan efficacy in triple negative breast cancer patient derived xenografts." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1986. http://dx.doi.org/10.1158/1538-7445.am2024-1986.
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Abstract Sacituzumab Govitecan (SG) is an antibody drug conjugate that targets the epithelial glycoprotein Trop-2. SG has been approved for the treatment of patients with triple negative breast cancer (TNBC) or estrogen receptor positive (ER+) breast cancer after they have received at least two previous systemic treatments. The objectives of this study were to identify biomarkers of SG response using breast cancer patient-derived xenografts (PDXs) and determine if SG efficacy changes when cells become carboplatin resistant (CR). Analysis of transcriptomic and proteomic levels of Trop2 using bulk RNAseq, scRNA-seq, and tandem mass tag spectrometry found that overall ER+ PDXs had significantly lower RNA (p-value less than 0.001) and protein (p-value less than 0.001) expression of Trop-2 than TNBC PDXs. Immunohistochemical assessment of 42 TNBC and 27 ER+ patient tumor samples identified variation in Trop-2 expression; within each cohort, expression varied from highly positive to completely negative. To test the association of Trop-2 with drug responsiveness, cells from 19 different PDXs were cultured in vitro and administered increasing doses of SG. TNBC cells were more responsive to SG treatments compared to ER+ cells (p-value equaling 0.005). Correlation analysis identified a positive relationship of drug response with protein abundance which was stronger in TNBC samples. In vivo studies with 7 TNBC PDXs found that over 70% were highly susceptible to SG treatments, with some tumors being completely eradicated or exhibiting a total inhibition of tumor growth which resulted in a long-term durable response after 10 weeks of treatment. In vivo across all the PDXs, Trop-2 expression alone did not strongly correlate with SG treatment success. Interestingly, CR sublines derived from 2 carboplatin sensitive PDXs were significantly less responsive to SG than their parental PDXs (p-value less than 0.001). These two CR sublines were also significantly less sensitive to the majority of 555 other drugs identified by the NCI compared to their parental PDXs. Ongoing studies are defining mechanisms of reduced SG efficacy in CR models. Overall, these studies find that SG is highly effective in many TNBC PDX models and should be utilized earlier in treatment protocols, especially in metastatic patients. Citation Format: Carson J. Walker, Julia E. Altman, Emily K. Zboril, Rachel K. Myrick, Nicole S. Hairr, David C. Boyd, Bin Hu, Mikhail G. Dozmorov, J. Chuck Harrell. Acquisition of carboplatin resistance corresponds with reduced sacituzumab govitecan efficacy in triple negative breast cancer patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1986.
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Juric, Dejan, Caroline Weipert, Leslie Bucheit, Rebecca Nagy, Justin Odegaard, Junhua Yu, Nicole Zhang, and Jiemin Liao. "Abstract P1-18-07: Impact of PIK3CA mutation (PIK3CA-mt) clonality on alpelisib (ALP) activity based on real-world evidence (RWE) following liquid biopsy testing." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–18–07—P1–18–07. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-18-07.
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Abstract Background:ALP is an alpha-selective PI3K-inhibitor approved in combination with fulvestrant for PIK3CA-mt HR+/HER2- advanced breast cancer (aBC). These mutations may either be truncal (clonal) or acquired (subclonal) under treatment pressure; however, data regarding the efficacy of ALP in these two populations are currently limited. This study utilized RWE to assess how the PIK3CA genomic environment impacts ALP response. Methods: RWE was sourced from the GuardantINFORM (Guardant Health) database, which comprises aggregated commercial payer health claims and de-identified records from over 100,000 individuals with comprehensive ctDNA results via Guardant360 (G360). All HR+/HER2- aBC patients with one or more of the 11 PIK3CA-mt cited in the Therascreen PIK3CA RGQ PCR Kit ALP companion diagnostic approval (P190001) identified on a G360 since May 2019 were included. Patients must have had at least one claim of ALP after the index G360 test. Patients who received ALP claim(s) in the six months prior to their G360 test were excluded. PIK3CA-mt were defined by clonal fraction (copy number-adjusted PIK3CA mutation allelic fraction/maximum somatic mutation allelic fraction) >50% (clonal) or ≤50% (subclonal). Real-world time to discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed as proxies for progression free survival. Log-rank tests were used to assess differences in rwTTD and rwTTNT and Chi-squared tests were used to compare the proportion of PIK3CA-mt and other co-occurring alterations between patients with only clonal and only subclonal PIK3CA-mt. Results:Of 223 eligible patients, 216 (96%) had no prior ALP exposure and were included for further analysis. Most patients had one PIK3CA-mt (199, 73%); 177 (82%) harbored only clonal mutations, 34 (16%) harbored only subclonal mutations, 5 (2%) harbored both. We saw no significant difference in rwTTD or rwTTNT for ALP in patients with clonal vs. subclonal PIK3CA-mt [median months to discontinuation = 5.0 (95% CI 4.0 - 6.9) vs. 7.4 (95% CI 3.7 - 11.1) p=0.82; median months to next treatment =7.0 (95% CI 5.5-9.4) vs. 9.0 (95% CI 4.0-12.6) p=0.81]. We observed no significant differences in the frequency of co-occurring alterations between samples with clonal vs. subclonal PIK3CA-mt (Table 1). Many alterations known to be associated with resistance to ALP and/or CDK4/6 inhibitors were identified, including RB1 and PTEN loss of function mutations. Patients with only subclonal PIK3CA-mt had a significantly higher proportion of E545K and E545G alterations compared to patients with only clonal PIK3CA-mt (E545K: 44% vs 26%, p=0.03; E545G: 6% vs 1%, p=0.017). Conclusions:Examination of RWE in patients treated with ALP after identification of PIK3CA-mt on G360 showed no significant difference in treatment outcomes or co-occurring mutations for clonal vs. subclonal PIK3CA-mt, suggesting that patients with PIK3CA-mt should be considered for ALP therapy irrespective of mutation clonality. While this study focused on outcomes related to PIK3CA hotspot alterations, a significant percentage of patients have PIK3CA non-hotspot alterations; assessment of ALP outcomes in this population is warranted. Table 1.Frequency of co-occurring alterations by PIK3CA-mt clonalityGeneClonal (N=177)Subclonal (N=34)p valueNo.%No.%TP538649%1441%0.428ESR18146%1338%0.419ATM3319%926%0.295EGFR3218%824%0.458RB12514%412%0.714PTEN2212%412%0.914FGFR12112%515%0.644FGFR22011%412%0.938MET1810%26%0.434SMAD4169%13%0.232ARID1A158%515%0.256APC148%39%0.858BRAF148%26%0.683GATA3137%26%0.761KRAS137%39%0.765BRCA1127%39%0.671KIT116%13%0.450CDK12106%13%0.515AR85%39%0.301BRCA285%26%0.732 Citation Format: Dejan Juric, Caroline Weipert, Leslie Bucheit, Rebecca Nagy, Justin Odegaard, Junhua Yu, Nicole Zhang, Jiemin Liao. Impact of PIK3CA mutation (PIK3CA-mt) clonality on alpelisib (ALP) activity based on real-world evidence (RWE) following liquid biopsy testing [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-07.
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Mukhopadhyay, Satabhisa, Tathagata Dasgupta, Elizabeth Walsh, Rebecca Millican-Slater, Andrew hanby, Joanne Stephenson, Craig A. Bunnell, and Nicolas M. Orsi. "Abstract P3-05-48: Prediction of disease recurrence in low risk Oncotype Dx breast cancers from digital H&E-stained whole slide images of pre-treatment resections alone." Cancer Research 83, no. 5_Supplement (March 1, 2023): P3–05–48—P3–05–48. http://dx.doi.org/10.1158/1538-7445.sabcs22-p3-05-48.
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Abstract Background Breast cancer patients with estrogen receptor (ER)+/HER2- (and usually node-negative) tumors can avail themselves of Oncotype DX Breast Recurrence Score (ODXRS) testing to predict their risk of distant recurrence within 9 years and, consequently, putative chemotherapy benefit. However, ODXRS testing requires sufficient tumour availability and specimen shipping, which imposes time and financial burdens to testing which have to be met by healthcare systems. The advent of digital pathology offers a potential avenue for exploring computer-aided diagnostic solutions which may overcome these hurdles by extracting the requisite information from hematoxylin and eosin (H&E)-stained tissue whole slide images (WSIs) alone. In turn, this technology could significantly reduce diagnostic turnaround times and cost, and improve accessibility and test reproducibility, thereby enabling healthcare systems to run more efficiently and offer patients more timely results. Ideally, such a platform should incorporate a measure of the underlying tumor biology to provide a fully explainable, white box solution, and may offer further insights into the identification of early recurrence events. Aims The aim of this study was to establish whether our computer-aided solution’s (Q-Plasia OncoReader Breast, QPORB) digital biomarker representing G1/S cell cycle deformations extracted from H&E WSIs was prognostic for disease-free survival (DFS) and could predict disease recurrence, particularly in the setting of low risk ODXRS breast cancers. Methods Primary breast cancer resection/excision specimens (n=70 cases) sent for ODXRS testing from St James’s University Hospital, UK (2016-2019) were collected. Anonymised diagnostic glass slides (n=198 slides) of H&E-stained tumors were scanned at x20 magnification on an Aperio AT2 scanner. In parallel, relevant clinical and histological data were collected from pathology reports and electronic patient records, including both ODXRS and recurrence events during follow-up. The QPORB recurrence scale (QPORB-RS), which combines statistical physics and tumor biology to identify image-based malignant cell cycle deformation, extracts prognostic information from WSIs. The contribution of potential confounders (age, stage, grade, lesion size, Nottingham prognostic index and Charlson score) were accounted for. Results The QPORB-RS was prognostic for DFS for patients with predominantly node-negative (including node micro-metastases) HR+/HER2- tumors over a median follow-up period of 5 years (P=0.02; dichotomized Kaplan Meyer with median cut-off). The QPORB-RS concurred with ODXRS’s high vs. low recurrence risk in 73% (19/26) and 61% (27/44) of cases, respectively, with an overall agreement of 66% (46/70). Moreover, the QPORB-RS identified all 5 patients who had recurrences (with ODXRS of 6, 9, 10, 21 and 26, and ages of 55, 66, 42, 35 and 50 years, respectively) as being high risk in the subset of those given a low (including historically intermediate) ODXRS and who did not receive chemotherapy. Conclusion The QPORB-RS is a good prognostic test of risk of disease recurrence in breast cancer patients with predominantly node-negative (including node micro-metastases) HR+/HER2- tumors within a median 5-year follow-up period. Our efforts are now focussed on extending this cohort and establishing the prognostic value of the QPORB-RS across all breast carcinomas, regardless of molecular subtype, stage/node positivity and menopausal status. Citation Format: Satabhisa Mukhopadhyay, Tathagata Dasgupta, Elizabeth Walsh, Rebecca Millican-Slater, Andrew hanby, Joanne Stephenson, Craig A. Bunnell, Nicolas M. Orsi. Prediction of disease recurrence in low risk Oncotype Dx breast cancers from digital H&E-stained whole slide images of pre-treatment resections alone [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-48.
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Sukumar, Jasmine S., Sagar Sardesai, Andy Ni, Nicole Williams, Bhuvaneswari Ramaswamy, Robert Wesolowski, Mathew A. Cherian, et al. "Abstract P1-02-03: Real World Treatment Patterns of Adjuvant Endocrine Therapy and Ovarian Suppression in Premenopausal HR+/HER2+ Breast Cancer." Cancer Research 83, no. 5_Supplement (March 1, 2023): P1–02–03—P1–02–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-02-03.
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Abstract Background: Approximately 10% of breast cancers (BC) are hormone receptor positive (HR+) and HER2 positive (HER2+). Despite treatment advances in the modern era of HER2 targeted therapies for early-stage disease, there remains a risk for late relapses. However, the role of adjuvant endocrine therapy (ET) to reduce recurrence in this BC subtype is unclear. Oncologists employ clinical judgment given lack of consensus, resulting in differences in treatment patterns. The ideal endocrine agent including the role of adding ovarian suppression (OS) in premenopausal women is unknown. These patients are largely underrepresented in clinical trials such as the phase III SOFT and TEXT studies. Additionally, these trials were initiated prior to the widespread use of trastuzumab with chemotherapy, which is now standard of care for HER2+ disease. We aimed to describe real world patterns surrounding choice of adjuvant ET and clinicopathologic features which predicted treatment with OS in premenopausal women with HR+/HER2+ BC. Methods: We performed a multi-institutional retrospective analysis of premenopausal women with non-metastatic HR+/HER2+ BC in the American Society of Clinical Oncology CancerlinQ® Discovery database from January 2010 to May 2020. Electronic health record data was obtained from 74 participating academic and community oncology sites. We collected clinical data on women less than 50 years who received chemotherapy, anti-HER2 therapy (trastuzumab with or without pertuzumab), and ET. Adjuvant OS was defined as receipt of at least 6 months of goserelin or leuprolide or surgical bilateral oophorectomy. Demographics, clinical characteristics, and treatment history was collected. Patients were categorized into 1 of 4 groups based on type of adjuvant ET prescribed at treatment initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression was conducted to assess the association between clinicopathologic features and OS use. Results: Out of 360,540 patients with invasive breast cancer in the database, 937 met inclusion criteria. Mean age was 41.7 (SD 5.9) years; 83% had stage 1 or 2 BC and 78% had node positive disease. The majority (n=818, 87%) were prescribed tamoxifen whereas only 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS, and AI + OS, respectively. Table 1 includes demographic and clinical characteristics of the cohort. No clinicopathologic features predicted OS use apart from age; patients ≥35 years were less likely to receive OS compared with those < 35 (p< 0.001) (table 2). Conclusion: To our knowledge, this is the first real world study evaluating OS treatment in HR+/HER2+ BC. The use of OS was uncommon; this suggests a perception of its limited benefit when added to HER2-targeted therapy. Most patients received tamoxifen as the ET of choice. Age was the only factor to predict OS treatment; high risk features including node positivity and higher stage was not associated with its use. This highlights the wide variability in real world practice surrounding the clinical indications for OS. Further investigation is warranted to characterize the utility of ET including addition of OS to prevent recurrence in premenopausal HR+/HER2+ BC. This will better inform a personalized approach to tailor therapy for optimal outcomes in this distinct BC subtype. Table 1. Demographic and clinical characteristics of study participants by endocrine therapy treatment group. Table 2. Multivariable logistic regression model of clinicopathologic characteristics to predict use of ovarian suppression. Citation Format: Jasmine S. Sukumar, Sagar Sardesai, Andy Ni, Nicole Williams, Bhuvaneswari Ramaswamy, Robert Wesolowski, Mathew A. Cherian, Daniel Stover, Margaret Gatti-Mays, Ashley C. Pariser, Preeti K. Sudheendra, Mridula A. George, maryam lustberg. Real World Treatment Patterns of Adjuvant Endocrine Therapy and Ovarian Suppression in Premenopausal HR+/HER2+ Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-03.
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Pontolillo, Letizia, Eleonora Nicolò, Laura Munoz Arcos, Carolina Reduzzi, Mara Serena Serafini, Amanda Kaylan Strickland, Nadia Bayou, et al. "Abstract PO3-14-11: Association between BRCA alterations detected by circulating tumor DNA and germline mutations in breast cancer patients: a retrospective mono-institutional analysis." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO3–14–11—PO3–14–11. http://dx.doi.org/10.1158/1538-7445.sabcs23-po3-14-11.
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Abstract Background: PARP inhibitors (PARPi) are a standard of care for breast cancer (BC) patients (pts) with germline BRCA (gBRCA) mutation, with benefit demonstrated also in patients with somatic (s) BRCA1/2 mutations. The use of circulating tumor (ct) DNA testing allows to detect resistant and actionable alterations in BC, but it could be associated with the incidental identification of germinal mutations. The aim of this study was to describe the incidence of both, somatic and germinal BRCA1/2 alterations, and the impact on the therapeutic outcomes in a retrospective BC cohort with clinical ctDNA testing for their BC. Materials and methods: A retrospective cohort of 245 BC pts that underwent ctDNA analysis (Guardant 360) between August 2014 and May 2023 at Weill Cornell Medical College was identified. Pts with at least a BRCA1/2 alteration, including variant of uncertain significant (VUS) and synonymous, were enrolled in the study. A descriptive analysis was performed. Results: Among 35 patients included, 34 had metastatic disease, the median age was 61 years old (IQR 40-67), and 65.7% were post-menopausal at diagnosis. 57.1% of pts had hormone receptor positive/HER2 negative (HR+/HER2-) BC, 20% had HER2 positive disease and 22.9% were triple-negative (TN) BC. Ten (28.6%) and 20 (57.1%) pts had a sBRCA1 or a sBRCA2 alteration on ctDNA, respectively; 5 pts (14.3%) had a coexisting sBRCA1/2 mutation. The median variant allele frequency (VAF) was 1.2% for BRCA1 and 2.7% for BRCA2 alterations. Furthermore, 53.3% and 6.7% of sBRCA1 and 40% and 8% of sBRCA2 mutations were identified as VUS and synonymous, respectively. The most common associated genomic alterations included TP53 (62.9%), ESR1 (20%) and PI3KCA (52%) with a median number of 4 variants (IQR 2-7). Next generation sequencing (NGS) testing on tissue was available for 3 patients: two demonstrated concordance with BRCA alterations detected by ctDNA, whereas no alteration in BRCA1/2 genes was found for the third patient despite the tissue analysis was performed at the same time of the ctDNA. Germline testing was available for 24 (69%) pts; a corresponding gBRCA1 mutation was found for 3 pts (VAF 48.6%-84.3%), and a gBRCA2 for 8 pts (VAF 26.7%-49.5%). Due to the small sample size, a univocal VAF cut-off to detect gBRCA1/2 mutations could not be calculated. Twenty-nine pts had a sBRCA1/2 mutation detected by ctDNA test before starting a new therapy; of these 55.2% had HR+/HER2- disease, while 17.2% and 27.6% were HER2 positive and TN BC, respectively. The median progression free survival (mPFS) was 10.3 (3.2-17.4) months (ms) and the 1-year and 2-year overall survival (OS) rates were 82.3% and 70.5%, respectively. The mPFS was 10.3 ms (0-25.0) for patients (n=16) that underwent chemotherapy, 5.6 ms (0-15.1) for those who had received endocrine therapy (n=9), and not reached for patients treated with PARPi (n=4). Conclusions: ctDNA analysis allows the detection of sBRCA1/2 mutations that could be missed by tissue-based testing. The identification of BRCA alterations on ctDNA could guide the use of germline testing even when these are present at a lower VAF than expected, with relevant impact on the therapeutic choices and family screening. Further evaluation to establish the impact of sBRCA1/2 detected by ctDNA on the therapeutic algorithm decision are needed. Citation Format: Letizia Pontolillo, Eleonora Nicolò, Laura Munoz Arcos, Carolina Reduzzi, Mara Serena Serafini, Amanda Kaylan Strickland, Nadia Bayou, Jeannine Donahue, Elisabetta Molteni, Lorenzo Gerratana, Diana Giannarelli, Eleni Andreopoulou, Emilio Bria, Massimo Cristofanilli. Association between BRCA alterations detected by circulating tumor DNA and germline mutations in breast cancer patients: a retrospective mono-institutional analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-11.
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Wierdl, Monika, Jerrel L. Catlett, Nicole Ocasio-Martinez, Jon D. Johnson, Amy Herman, Neekesh V. Dharia, Gabriela Alexe, et al. "Abstract 3949: SMARCAL1 is a novel synthetic lethal target in ALT+ osteosarcoma and neuroblastoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3949. http://dx.doi.org/10.1158/1538-7445.am2024-3949.
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Abstract Osteosarcoma (OS) is an aggressive pediatric solid tumor that is difficult to treat with established therapies. We performed CRISPR/Cas9 screening in 13 OS cell lines as part of the Dependency Map project. Mining this data to identify genes whose knockout (KO) leads to selective anti-viability in OS, we observed the helicase SMARCAL1 as a selective dependency in OS (p<0.0001; effect size = -0.275). Given the genomic instability of OS and SMARCAL1’s related, established role in replication stress, we first validated our screens by CRISPR KO in OS lines in vitro. This demonstrated selective antiviability of SMARCAL1 KO in dependent OS lines. To orthogonally validate SMARCAL1 dependency, we deployed a dTAG system, utilizing a hetero-bifunctional small molecule targeting the tagged protein for degradation by an E3 ubiquitin ligase. We observed antiviability of dependent lines after SMARCAL1 degradation. In parallel, in order to ascertain importance of this gene in vivo, we performed a barcoded CRISPR pooled screen against pre-selected OS dependencies in an OS cell line xenograft in NSG mice. After sequencing of tumor gDNA, we identified SMARCAL1 as a top hit, suggesting relevance in vivo.We next investigated biomarkers of SMARCAL1 dependency. A role for SMARCAL1 has been described in alternative lengthening of telomeres (ALT). We asked whether ALT+ OS cell lines are enriched for SMARCAL1 dependency. We found a correlation between ALT+ OS and SMARCAL1 dependence in our CRISPR screens. We then asked if this extends to other ALT+ tumors. Neuroblastoma (NB), the most common extracranial pediatric solid tumor, is enriched for ALT. When we looked specifically at NB models, we observed that SMARCAL1 was the most enriched dependency in ALT+ NB compared with other NB lines (p<0.0001; effect size = -0.785). We then performed SMARCAL1 KO in 2 ALT+ ATRX-altered NB lines and one ALT+ ATRX-WT NB line. We found that SMARCAL1 KO led to antiviability in the ATRX-altered ALT+ cell lines, while the ALT+ ATRX-WT cell line was unaffected. This suggests that dependency on SMARCAL1 is specific to ATRX alteration, rather than ALT alone.In order to confirm synthetic lethality between ATRX and SMARCAL1, we next utilized a human OS line not included in the DepMap screen, which has biallelic inactivation of SMARCAL1. We infected this line with our SMARCAL1 dTAG, leading to constitutive overexpression of SMARCAL1, and then performed ATRX KO. We observed that SMARCAL1 overexpression rescued the antiviability effect of ATRX KO. This could be reversed by degradation of exogenous SMARCAL1, suggesting that ATRX and SMARCAL1 can compensate for one another. Taken together, these findings demonstrate that SMARCAL1 is a selective dependency engendered by the loss of WT ATRX in OS and NB and that SMARCAL1 is playing a critical role in mediating ALT. Studies are ongoing to determine the mechanism of SMARCAL1’s activity and potential for targeting this enzyme for therapeutic benefit. Citation Format: Monika Wierdl, Jerrel L. Catlett, Nicole Ocasio-Martinez, Jon D. Johnson, Amy Herman, Neekesh V. Dharia, Gabriela Alexe, E. Alejandro Sweet-Cordero, Emily Bernstein, Kimberly Stegmaier, Lillian M. Guenther. SMARCAL1 is a novel synthetic lethal target in ALT+ osteosarcoma and neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3949.
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Hyer, Marc L., Jimmy Fourtounis, David Gallo, Vivek Bhaskaran, Rino Stocco, Rosie Kryczka, Sai Save, et al. "Abstract C163: KRAS alterations combined with TP53 mutations as novel synthetic lethal genomic lesions for PKMYT1 inhibition." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C163. http://dx.doi.org/10.1158/1535-7163.targ-23-c163.
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Abstract Background: Membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) is a cell cycle regulatory kinase that inhibits CDK1/CyclinB activity, delaying entry into mitosis in tumor cells experiencing replication stress (RS). RS is frequently induced by genetic alterations that drive premature transition from G1 to S phase, promoting genome instability and creating a synthetic lethal (SL) relationship between these specific alterations and PKMYT1 inhibition. This relationship has been demonstrated preclinically and clinically with CCNE1 amplification and FBXW7 mutations, common alterations in ovarian and colorectal cancers, respectively. Oncogenic KRAS gain of function (GOF) mutations, combined with TP53 alterations, are bona fide drivers of RS. Here we investigate the relationship between KRAS/TP53 alterations and PKMYT1 inhibition, mediated by the first-in-class, potent and selective PKMYT1 inhibitor lunresertib (RP-6306), alone or in combination with RS-inducing agents. Methods: KRAS/TP53 double mutant isogenic cell pairs, across relevant tumor origins, were genetically engineered to express multiple KRAS GOF mutant codons and alleles (G12D, G12C, G12V, G12R, G13D and Q61H). Cell cycle distribution perturbations and RS were evaluated. Sensitivity to lunresertib alone or in combination with chemotherapeutic or targeted agents was assessed by cell growth assays. In vitro findings were further evaluated in KRAS/TP53 double mutant patient-derived xenografts (PDX). Results: Lunresertib inhibited the growth of isogenic KRAS/TP53 double mutant cells, with up to a 12-fold EC50 shift compared to control parental cells. Combination of lunresertib with RS-inducing chemotherapeutic agents (eg. gemcitabine), or the ATR inhibitor camonsertib (RP-3500) led to synergistic cell growth inhibition in KRAS/TP53 mutant cells at significantly lower concentrations than in wild type lines. Mechanistically, KRAS/TP53 isogenic cells showed elongated S-phase and increased cyclin B1 levels, phenocopying the effects of CCNE1 amplification. Lunresertib induced premature mitosis and DNA damage in KRAS/TP53 mutant cells, sparing parental cell lines. PDX efficacy studies demonstrated robust combination benefit in pancreatic, lung and colorectal settings, with durable tumor regressions and complete responses observed. Conclusion: GOF KRAS mutations, when combined with TP53 alterations, show a strong SL relationship with PKMYT1 inhibition, alone or in combination with RS-inducing antitumor agents. Importantly, the SL phenotype was observed across multiple tumor indications and KRAS mutant codons/alleles, suggesting a potential broad scope of clinical utility beyond approved KRAS inhibitors. The mechanism is similar to CCNE1 amplification, characterized by enhanced G1/S transition driving heightened dependence on PKMYT1 to inhibit CDK1/CyclinB. Taken together, our data form rationale for the therapeutic evaluation of PKMYT1 inhibitors in KRAS/TP53 altered tumors and uncover a potential new patient selection biomarker for lunresertib. Citation Format: Marc L. Hyer, Jimmy Fourtounis, David Gallo, Vivek Bhaskaran, Rino Stocco, Rosie Kryczka, Sai Save, Helen Burston, Olivier Nicolas, Stephen Morris, Anne Roulston, Jordan T. F. Young, Michal Zimmermann, C. Gary Marshall, Artur Veloso, Elia Aguado-Fraile. KRAS alterations combined with TP53 mutations as novel synthetic lethal genomic lesions for PKMYT1 inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C163.
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Loibl, Sibylle, Jan Hauke, Karen Gelmon, Frederik Marmé, Corinna Ernst, Miguel Martin, Michael Untch, et al. "Abstract P5-13-36: Germline BRCA1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–13–36—P5–13–36. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-13-36.
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Abstract Background: In high-risk hormone-receptor (HR)+/HER2- BC patients germline (g) mutations can be found in approximately 14% in BRCA1/2 and in BRCA1/2 and other BC predisposition genes in 20% (Pohl-Rescigno E, et al. JAMA Oncol 2020). In metastatic BC CDK4/6 inhibitors may have greater activity in patients with a BRCA mutation detected in ctDNA (André F, et al. J Clin Oncol 2020). The PENELOPE-B trial did not to show an improved invasive disease-free survival (iDFS) by adding palbociclib to ET in high-risk HR+/HER2- BC (Loibl S, et al. J Clin Oncol 2021). Methods: Blood samples from 898 of 1250 PENELOPE-B patients were available. 445 patients were sampled following a case-cohort design (220 cases defined as patients with any event during follow-up and 225 randomly selected patients without any event [non-cases]) and analyzed for germline variants in BRCA1/2 and 16 non-BRCA1/2 cancer predisposition genes (ATM, BARD1, BRIP1, CDH1, CHEK2, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, XRCC2) by targeted next generation sequencing (NGS). The primary definition of mutational status was the prevalence of a pathogenic mutation (mt) in one or more analyzed BC predisposition genes. Statistical analyses for time-to-event endpoints (iDFS, distant disease-free survival [DDFS], and overall survival [OS]) were based on inverse probability weighting: weighted Cox proportional hazard models and Kaplan-Meier estimates were used. Results: 442 of 445 patients (placebo arm: 104 cases and 105 non-cases; palbociclib arm: 114 cases and 119 non-cases) were successfully analyzed for mutational status. A total of 42 (9.5%) patients (placebo arm: 9.1%; palbociclib arm: 9.9%) carried any mutation. 15 (3.4%) patients had a gBRCA1/2 mt (one of whom carried a gATM mt and one a gCHEK2 mt in addition to gBRCA2 mt) and 29 (6.6%) had mutations in one of the other BC predisposition genes (n=8 CHEK2, n=7 PALB2, n=5 ATM, n=2 RAD50, n=1 for BARD1, FANCM, MRE11A, RAD51C, RAD51D, TP53 and n=1 both RAD51D and BRIP1). The mutational status with respect to all genes analyzed showed no significant correlation to clinical baseline variables. With regard to gBRCA1 and gBRCA2 genes only, the mutational status significantly correlated with age but not with other clinical variables: all 15 (100%) gBRCA mt carriers were younger than 50 years compared to 238 (56%) wildtype (wt) patients (p=0.002). The iDFS rate after 3 years was 80.9% in patients with any mutation and 79.5% in patients without. Mutational status (mt vs. wt) based on all genes analyzed was not prognostic (iDFS: hazard ratio 1.015, 95%CI 0.558-1.784; DDFS: 0.970, 95%CI 0.521-1.758; OS: 0.768, 95%CI 0.274-1.615). Neither the mutated patients had a benefit from palbociclib treatment (palbociclib vs placebo; iDFS: hazard ratio 0.766, 95%CI 0.263-3.022; DDFS: 0.897, 95%CI 0.275-3.489; OS: 0.666, 95%CI 0.063-5.671) nor the wt patients (iDFS: hazard ratio 0.918, 95%CI 0.650-1.303; DDFS: 0.966, 95%CI 0.679-1.393; OS: 0.901, 95%CI 0.573-1.433); interaction tests for treatment arm/mutational status for all time-to-event endpoints were not statistically significant. Analysis in the subgroups of patients by gBRCA1/2 showed similar results but had less statistical power. Conclusions: In this case-cohort analysis of 442 patients enrolled in the PENELOPE-B trial, the detection of BC predisposition genes was lower than expected with 10%. This is probably due to the low rate of gBRCA1/2 carriers (3.4%), which could be influenced by the selection criteria of the trial. Patients with gBRCA1/2 or other BC disposition genes had a comparable outcome to non-carriers in the PENELOPE-B trial. Citation Format: Sibylle Loibl, Jan Hauke, Karen Gelmon, Frederik Marmé, Corinna Ernst, Miguel Martin, Michael Untch, Hervé Bonnefoi, Erik Knudsen, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Nicholas Turner, Agnieszka Witkiewicz, Federico Rojo, Peter A Fasching, José A García-Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Carsten Denkert, Michael Gnant, Andreas Makris, Yuan Liu, Olga Valota, Bärbel Felder, Karsten Weber, Valentina Nekljudova, Eric Hahnen. Germline BRCA1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-36.
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Radzimierski, Adam, Aneta Bobowska, Agata Stachowicz, Kamil Kuś, Kamila Kozłowska-Tomczyk, Agnieszka Ludwig-Słomczyńska, Paulina Podkalicka-Gołda, et al. "Abstract 4598: Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4598. http://dx.doi.org/10.1158/1538-7445.am2024-4598.
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Abstract Homozygous deletions of the p16/CDKN2a (cyclin dependent kinase inhibitor 2A) locus, which is responsible for regulating the cell cycle, are commonly found in cancer and often involve the deletion of adjacent genes. One such adjacent gene is methylthioadenosine phosphorylase (MTAP), involved in metabolism, located on chromosome 9p21 in close proximity to the p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme, competing with the substrate S-adenosylmethionine (SAM) required for methylation reactions. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced. This heightened sensitivity to modulation of methylosome activity makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Hence, selective targeting of PRMT5 in cancers with homozygous MTAP deletion represents a promising strategy for specifically eliminating cancer cells with this genetic alteration. Ryvu has developed MTA-cooperative PRMT5 inhibitors characterized by good drug-like physicochemical properties and inhibition of methyltransferase activity with IC50 values in the low nanomolar range. A structure-based lead optimization delivered compounds coming from two independent series with high selective potency in MTAP-deleted cell lines and DMPK profiles allowing an oral administration. The antitumor activities were compared in vitro and in vivo to MRTX1719 and AMG193 in MTAP null tumors such as HCT116 MTAP KO, DoHH-2 and Lu99. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies confirm that MTA cooperative PRMT5 inhibitors exert strong synthetic lethal phenotype in MTAP deleted cancers and offer an exciting therapeutic opportunity for a large patient population. Citation Format: Adam Radzimierski, Aneta Bobowska, Agata Stachowicz, Kamil Kuś, Kamila Kozłowska-Tomczyk, Agnieszka Ludwig-Słomczyńska, Paulina Podkalicka-Gołda, Aniela Gołas, Monika Żukowska, Pavlo Lebed, Przemysław Wyrębek, Daria Szukiel, Matylda Stefaniak, Oleksandr Popika, Julia Krzywik, Sujit Sasmal, Paulina Niedziejko-Ćwiertnia, Klara Korta-Piątek, Karolina Fijołkowska, Aleksandra Więckowska, Marta Olszak-Płachta, Swapnil Nipunge, Mateusz Świrski, Marek Wronowski, Henryk Pawlik, Quỳnh Vũ, Katarzyna Łagosz-Ćwik, Mateusz Stoszko, Szymon Woroszyło, Igor Tomczyk, Ewelina Gabor-Worwa, Nilesh Gaud, Anna Kowal-Chwast, Dawid Gogola, Magdalena Miodek, Róża Starczak, Agata Dudek, Jacek Faber, Bożena Winnik, Sanja Novak-Ratajczak, Agnieszka Świrska, Karolina Gluza, Paweł Guzik, Katarzyna Banaszak, Nicolas Boutard, Grzegorz Ćwiertnia, Krzysztof Brzózka, Mateusz Nowak, Anna Bartosik, Didier Pez. Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4598.
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Parikh, Milan, Ryan Park, Aparna R. Parikh, Julie L. Koenig, Leon Pappas, Moshe Sade-Feldman, Lynn Bi, et al. "Abstract 1194: Understanding radiation and immunotherapy induced cell state shifts in the pancreatic tumor microenvironment." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1194. http://dx.doi.org/10.1158/1538-7445.am2024-1194.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few effective treatment options. It is characterized by a highly desmoplastic tumor microenvironment and a paucity of dendritic cells, leading to low immune cell infiltration and poor outcomes with immunotherapy treatments that are highly effective in other cancers. In a recent pilot study, metastatic PDAC patients who had progressed on chemotherapy were treated with a combination of dual immune checkpoint blockade (ICB) therapy and radiation which resulted in an 18% overall response rate (ORR) and 29% disease control rate (DCR). This led to a phase 2 study in order to further test this combination with the goal of deep correlative analysis to understand the determinants of immunotherapy response and resistance. In this follow up there was a 3.6% ORR, 10.7% DCR, progression free survival (PFS) of 2.3 months, and a single patient with complete response. We collected 36 samples from 23 patients including primary pancreas tumor tissue and liver metastases, and 13 pairs of pre and on treatment biopsies. We performed single-nucleus and paired single-cell RNA and TCR sequencing on these samples to provide comprehensive insight into the cell types and biology present in this unique tumor microenvironment. Using supervised non-negative matrix factorization we have identified both previously established and novel gene programs that co-vary between cell types. Within the various tissue sites we have identified differing proportions of basal to classical tumor cell types and a distinct shift towards the classical state post-radiation. Of particular interest is a group of interferon related gene programs present within epithelial cell subtypes, C1QC+ and MHCII+ macrophages, and CD14+/CD16+ monocytes that indicate cell type specific responses to treatment. Focusing on the T cells, we found a distinct shift towards exhausted or proliferating states on treatment and using TCR sequencing data we have identified novel and expanding clones on treatment, largely consisting of those same cell subtypes. We also collected spatial transcriptomics data on a subset of patient samples, and analysis is ongoing to further confirm the cell type relationships identified in single-cell resolution data, along with spatial localization of basal to classical tumor states. This vast multimodal dataset allows us novel insight into the radiation and dual ICB induced cellular state shifts in the tumor microenvironment. Citation Format: Milan Parikh, Ryan Park, Aparna R. Parikh, Julie L. Koenig, Leon Pappas, Moshe Sade-Feldman, Lynn Bi, Nicole Carzo, Tarin M. Grillo, Islam Baiev, Olanike Asupoto, Irena Gushterova, Tom LaSalle, Anna Gonye, Emily Blaum, David P. Ryan, David T. Ting, Theodore S. Hong, Dana Pe'er, Nir Hacohen, Arnav Mehta. Understanding radiation and immunotherapy induced cell state shifts in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1194.
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Yadav, Monica, Jeeyeon Lee, Peter Haseok Kim, Seyoung Lee, Taegyu Um, Salie Lee, Maria Jose Chuchuca, et al. "Abstract 7530: Harmonization radiomics models to predict tumor response in non-small cell lung cancer (NSCLC) patients treated with immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7530. http://dx.doi.org/10.1158/1538-7445.am2024-7530.
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Abstract Background: Precise prediction of immunotherapy response in non-small cell lung cancer (NSCLC) is crucial for personalized treatment. This study investigates the application of pretreatment CT-based radiomics and use of harmonization model in predicting these outcomes in NSCLC patients receiving immunotherapy. Methods: This retrospective study examined data from 152 stage III-IV NSCLC patients undergoing immunotherapy. Patient responses were categorized using immune-related RECIST (irRECIST) criteria into durable responders (complete response [CR], partial response [PR], or stable disease [SD]) for at least 24 weeks and non-responders. Tumor segmentation was performed using LIFEx software (IMIV/CEA, Orsay, France). 3D-radiomic features were extracted from both the tumor and surrounding 1 cm thick peritumoral regions. The Random Forest (RF) algorithm was employed to develop a classification model to differentiate between responders and non-responders. A harmonization model was deployed to account for the scanner-related differences by using spleen and normal lung signals. The dataset was divided into a training set (75%) and a test set (25%). Bootstrapping with 1,000 iterations was performed to estimate the model's performance by calculating the median and 95% confidence interval (CI) estimate. The accuracy of the model's predictions was evaluated by creating a confusion matrix. The model's performance was assessed by calculating the sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and area under the ROC curve (AUC) for response prediction. Results: A total of 152 patients were analyzed. 87 (57.23%) were female and 65 (42.76%) were male. The median age was 59 years. Histology types included were: 111 Adenocarcinoma (73%), 27 Squamous cell carcinoma (17.8%), and 14 other types (9.2%). The model achieved a sensitivity of 0.63, a specificity of 0.59, a PPV of 0.51, and NPV of 0.7 for response prediction of NSCLC patients receiving immunotherapy. The AUC of 0.61 indicates that the model may discriminate between responders and non-responders with an accuracy of 61%. Conclusion: This study demonstrates the potential of radiomics and the use of harmonization models to predict immunotherapy responses in NSCLC patients, offering insights into personalized treatment approaches. Larger studies are needed to validate our findings and the utility of harmonization models in predicting a tumor response. Citation Format: Monica Yadav, Jeeyeon Lee, Peter Haseok Kim, Seyoung Lee, Taegyu Um, Salie Lee, Maria Jose Chuchuca, Trie Arni Djunadi, Liam Il-Young Chung, Jisang Yu, Darren Rodrigues, Nicolo Gennaro, Leeseul Kim, Myungwoo Nam, Youjin Oh, Sungmi Yoon, Zunairah Shah, Yuchan Kim, Ilene Hong, Jessica Jang, Grace Kang, Amy Cho, Soowon Lee, Timothy Hong, Cecilia Nam, Yury S Velichko, Young Kwang Chae. Harmonization radiomics models to predict tumor response in non-small cell lung cancer (NSCLC) patients treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7530.