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Wheeler, Nicholas J. "Book Review: George J. Andreopoulos, Genocide: Conceptual and Historical Dimensions (Philadelphia, PA: University of Pennsylvania Press, 1994, 265 pp., no price given)." Millennium: Journal of International Studies 25, no. 1 (March 1996): 154–56. http://dx.doi.org/10.1177/03058298960250010903.
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Kien, C. Lawrence. "Book Reviews: NUTRITIONAL CARE FOR HIGH RISK NEW-BORNS, Ohio Neonatal Nutritionists. George F. Stickley Company, Philadelphia, PA, 1985, 214 pp, $17.50." Journal of Parenteral and Enteral Nutrition 11, no. 4 (July 1987): 428–29. http://dx.doi.org/10.1177/014860718701100420.
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Drell, Joanna H. "Florence and Its Church in the Age of Dante. By George W. Dameron. (Philadelphia, Pa.: University of Pennsylvania Press, 2005. Pp.x, 374. $65.00.)." Historian 70, no. 4 (December 1, 2008): 828–29. http://dx.doi.org/10.1111/j.1540-6563.2008.00227_52.x.
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Yang, Li, Jae Young So, Nicolas Skrypek, Anand Merchant, George Nelson, Howard Yang, and Maxwell Lee. "Abstract P1-05-08: Targeting tumor heterogeneity and breast cancer metastasis through the metastatic microenvironment mediated epigenetic reprogramming." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–05–08—P1–05–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-05-08.
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Abstract Targeting tumor heterogeneity and breast cancer metastasis through the metastaticmicroenvironment mediated epigenetic reprogrammingLi Yang and Jae Young So, Nicolas Skrypek, Anand Merchant, George Nelson, Howard H.Yang, Maxwell P. LeeNational Cancer Institute, National Institutes of Health, Bethesda, MD 20892Current cancer treatments are largely based on the genetic characterization of primarytumors and are ineffective for metastatic disease. There is lack of mechanistic understanding ashow cancer cells are selected and evolved to establish distant metastatic colonies. In addition,tumor heterogeneity and biomarker identification remain to be some of the most difficultchallenges in cancer treatment. In the current study, we discovered an increased DNAmethyltransferase 3B (DNMT3B) in metastatic nodules and in tumor cells with epithelia tomesenchymal (EMT) phenotype. Of great interest, high levels of DNMT3B were correlated withpoor clinical outcomes in multiple human breast cancer datasets. Mechanistically, DNMT3Balters multiple pathways including STAT3, NFkappaB, PI3K/Akt, beta-catenin, Notch signalingas well as EMT, which are critical for cancer cell survival, apoptosis, proliferation, invasion, andcolonization. We further identified PGE2 and IL6 as critical inflammatory mediators inDNMT3B induction. Importantly, targeting IL6 or PGE2 production reduced DNMT3Bexpression and improved chemo treatment or PD1 immune therapy. Furthermore, perioperative(surgical removal of primary tumors) targeting DNMT3B in combination with chemotherapymarkedly suppressed tumor recurrence and metastasis in preclinical mouse models for triplenegative breast cancer. Our studies identify DNMT3B as an important mechanism fortranscription regulation in tumor heterogeneity that is critical for tumor invasion and metastasis,thus suggesting a validated target for treating metastatic disease. Citation Format: Li Yang, Jae Young So, Nicolas Skrypek, Anand Merchant, George Nelson, Howard Yang, Maxwell Lee. Targeting tumor heterogeneity and breast cancer metastasis through the metastatic microenvironment mediated epigenetic reprogramming [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 P1-05-08.
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Eksi, Ece Sebnem, Zeynep Sayar, Alex Chitsazan, George T. Thomas, Andrew Adey, Paul T. Spellman, and Ryan Kopp. "Abstract 999: Epigenetic loss of heterogeneity from low to high grade localized prostate tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 999. http://dx.doi.org/10.1158/1538-7445.am2022-999.
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Abstract Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequenced the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumors. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumors. Despite this loss, high-grade tumors exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory program. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumors. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumors, critical for molecular stratification of the disease. Citation Format: Ece Sebnem Eksi, Zeynep Sayar, Alex Chitsazan, George T. Thomas, Andrew Adey, Paul T. Spellman, Ryan Kopp. Epigenetic loss of heterogeneity from low to high grade localized prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 999.
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Doucet, Brian. "Driving Detroit: The Quest for Respect in the Motor City. by George Galster 2012. Philadelphia, PA: University of Pennsylvania Press. 328 pp. ISBN 978-0-8122-4429-8." Tijdschrift voor economische en sociale geografie 105, no. 3 (June 6, 2014): 368–69. http://dx.doi.org/10.1111/tesg.12089.
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D'Rozario, Joshua, Julie George, and Roman Thomas. "Abstract 6028: Patient derived organoids demonstrate hallmark characteristics of small cell lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6028. http://dx.doi.org/10.1158/1538-7445.am2022-6028.
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Abstract Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers with an overall 5-year survival rate of 5-10%. Although transgenic mouse models and patient derived xenograft models have been shown to capture the heterogeneity and complexity of SCLC, the costs involved and timeframe of generating these models can be extensive. Furthermore, these models lack the ability to study the patients’ immune components and tumor microenvironment. Alternatively, in other cancer types in vitro methods to generate organoids have been successful in the hope to develop personalized patient derived organoids for screening and further downstream analyses. Here, we have generated and characterized small cell lung cancer patient-derived tumor organoids and confirmed that the organoids possess similar molecular characteristics, genetic profiles and morphological architectures to the corresponding patient tumor tissue. Organoids were shown to express hallmark features for SCLC, which included expression of neuroendocrine markers CD56, CHGA, INSM1 and SYP shown by immunohistochemistry. We suggest utilizing these organoids as SCLC patient models would be ideal for investigating the tumor microenvironment in SCLC, mechanisms between tumor immune cell interactions as well as assessing patients’ responses to therapy. Citation Format: Joshua D'Rozario, Julie George, Roman Thomas. Patient derived organoids demonstrate hallmark characteristics of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6028.
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Ku, Amy T., Adelaide Young, Ahmed A. Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C. Williams, et al. "Abstract P007: Short-term PI3K inhibition prevents breast cancer in preclinical models." Cancer Prevention Research 16, no. 1_Supplement (January 1, 2023): P007. http://dx.doi.org/10.1158/1940-6215.precprev22-p007.
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Abstract Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of breast precancerous lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer. Citation Format: Amy T. Ku, Adelaide Young, Ahmed A. Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C. Williams, Bryant McCue, George Miles, Chandandeep Nagi, Fariba Behbod, Yi Li. Short-term PI3K inhibition prevents breast cancer in preclinical models. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P007.
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Calin, George A. "Abstract IA025: About motifs, non-codingRNAs and metastases." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): IA025. http://dx.doi.org/10.1158/1538-7445.metastasis22-ia025.
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Abstract MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies. Citation Format: George A. Calin. About motifs, non-codingRNAs and metastases [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA025.
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Sanchez-Covarrubias, Alex P., Ramlogan Sowamber, Leah Dodds, Andre Pinto, Sophia George, and Matthew Schlumbrecht. "Abstract C052: Endometrial cancer genomics varies by race." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C052. http://dx.doi.org/10.1158/1538-7755.disp22-c052.
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Abstract Introduction Variability in endometrial cancer (EC) risk and outcomes exist, with Black women disproportionately negatively affected related to White women. The biologic etiologies of these observations are poorly understood. Our objective was to describe the somatic mutations of the tumor genome and compare them to RNA expression in self-identified Black and White women diagnosed with EC. Methods Women with newly diagnosed EC and undergoing hysterectomy were recruited prospectively. Fresh tumors obtained at the time of surgery were flash-frozen, underwent DNA and RNA extraction and were submitted for whole exome sequencing (WES) analysis (DNA) or bulk RNA sequencing analysis. Differentially expressed genes between racial groups and tumor grade were calculated using Deseq2. Genomic ancestry was determined using ADMIXTURE. Chi-square and Mann Whitney U tests were used for analyses, with a threshold for significance of p<0.05. Results A total of 49 patients with EC were included. Thirty (61.2%) women were diagnosed with low-grade EC and 19 (38.8%) with high grade EC. Twenty (40.8%) women self-identified as Black, 27 (55.1%) as White and 2 (4.1%) as Asian/other. Admixture analysis showed that 36 (73.4%) had >14% African ancestry. The remaining 13 (26.5%) patients had admixed European and Native American ancestry, with <1% African ancestry. In the RNA-seq, we found significant DEGs by tumor grade; with 2132 DEG in High grade compared to Low grade tumors with a false discovery rate of <0.05 and a fold change (FC) of ≤-1.5 or ≥1.5. Top 10 DEG included MT4, TAF15, SLFN5 and PLEKHS1 (upregulated) and MCRIP1, MAZ, MYOM3, PRPH, BCL7C, AC016700.5 (downregulated). In the WES analysis, 8 Black women had mutations in GON4L compared to 1 in the White woman (44.4% vs 3.7%, padj=0.04); and 7 Black women had a mutation in PRAMEF14 compared to 1 White woman (38.8% vs 3.7%, padj= 0.06). Conclusion GON4L, which is a transcription factor associated with decreased apoptosis and promotion of tumor growth through CD24 regulation, was significantly more mutated in the EC genome of Black women relative to White women. Somatic mutation and transcriptional changes are seen between tumor grade and self-identified race and require further exploration for its relationship to aggressive disease. Citation Format: Alex P. Sanchez-Covarrubias, Ramlogan Sowamber, Leah Dodds, Andre Pinto, Sophia George, Matthew Schlumbrecht. Endometrial cancer genomics varies by race [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C052.
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Wilkie, Diana J., George Fitchett, Tasha M. Schoppee, Marvin O. Degado Guay, Joshua Hauser, Sheri M. Kittelson, Sean O-Mahony, et al. "Abstract A032: Dignity therapy effects by race: Chaplain and nurse implementation in pragmatic, multisite stepped-wedge randomized control trial." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): A032. http://dx.doi.org/10.1158/1538-7755.disp22-a032.
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Abstract Aim: As a brief psychotherapy for individuals facing mortal threat, Dignity Therapy (DT) effects on spiritual outcomes are unknown, especially as an intervention to support cancer health equity for racial minority patients. Our study aim was to compare usual outpatient palliative care and such care along with nurse-led or chaplain-led DT groups for main effects on dignity impact and the interaction of DT with race. Methods: We conducted the 4-step, stepped-wedge randomized control trial at 4 NCI designated cancer centers and 2 academic cancer centers across the United States. Half of the sites were randomized to chaplain-led DT and half to nurse-led DT. Of the 645 recruited cancer patients (age ≥ 55 years) receiving outpatient palliative care, 579 (59% female, mean age 66.4±7.4 years, 78% White, 77% Christian religion, 62% stage 4 cancer) provided data for intent-to-treat analysis. Over 6 weeks, patients completed pretest/posttest measures including the Dignity Impact Scale (DIS, primary outcome) ranging from low impact of 7 to highest impact of 35. In step 1-3, study procedures were completed in person. In step 4 (during the COVID-19 pandemic), when all sites were providing the intervention, study procedures were completed via Zoom. We used multiple imputation and regression analysis adjusting for pretest DIS, study site, and study step. Results: Of the 579 patients, 317 were in the DT group and 262 in the usual care group. The vast majority of the sample was White (n=448) along with 103 Blacks, 5 Asians, 2 Pacific Islanders, 1 Native American, 13 other races (all minorities were combined as Other Race), and 7 were missing race data. At pretest, the mean DIS score was 24.3±4.3 in the DT group and 25.9±4.3 in the usual care group. Adjusting for pretest DIS scores, study site, and study step, the chaplain-led (β=1.7, p=.02) and nurse-led (β=2.1, p=.005) groups reported significantly higher posttest DIS scores than the usual care groups. Adjusting for age, gender, race, education, and income, the effect on DIS scores remained significant for both DT groups. We then examined the interaction between race and DT with the entire sample and observed that the interaction was not significant (p=.73) and the sizes of DT effects were similar for White (β=1.9, p=.005) and the Other Race (β=1.6, p=.055) patients. Conclusions: Whether led by chaplains or nurses, DT was effective in improving dignity impact for older adult outpatient palliative care patients with cancer. DT, a patient-centered approach, has promise as an intervention to improve health equity in support of dignity for racial minorities. This rigorous trial of DT is a landmark step in gero-oncology palliative care and spiritual health services research focused on cancer health equity. Citation Format: Diana J. Wilkie, George Fitchett, Tasha M. Schoppee, Marvin O. Degado Guay, Joshua Hauser, Sheri M. Kittelson, Sean O-Mahony, Michael W. Rabow, Tammie E. Quest, Sheldon Solomon, Yingwei Yao, George Hadzo, Harvey Max Chochinov, Linda L. Emanuel. Dignity therapy effects by race: Chaplain and nurse implementation in pragmatic, multisite stepped-wedge randomized control trial [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A032.
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George, Jason T. "Abstract 2740: Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2740. http://dx.doi.org/10.1158/1538-7445.am2022-2740.
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Abstract The lack of durable therapeutic interventions continues to limit cancer treatment efficacy. While breakthroughs in immunotherapy have improved patient survival for some disease subtypes, immune escape is an unfortunate and common hallmark of cancer evasion. Understanding the dynamic interplay between an evolving and heterogeneous malignant population and the adaptive immune system, consisting of millions of unique T cells, is therefore required for designing optimized treatment strategies. We begin by describing the implications of cancer escape via durable evasion events, such as major histocompatibility antigen presentation down-regulation. Durable escape is then applied to relate observed cancer age-specific incidence to physiologic impairments in T cell turnover and diversity. We then discuss a more generalized stochastic process that enables transient escape and recurrent recognition via distinct T cell subclones. This co-evolutionary model predicts repeated immune recognition and cancer evasion prior to disease manifestation. Using this model, we find that T cell turnover and cancer mutation rates explain differences in early age incidence data across nearly all cancer types. Lastly, we introduce a modeling approach for understanding the extent of optimality occurring in cancer evasion via tumor-associated antigen downregulation, emphasizing the utility of foundational modeling frameworks for optimizing cancer T cell immunotherapy. Citation Format: Jason T. George. Stochastic modeling uncovers the interplay between early cancer progression and adaptive immune-specific cancer escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2740.
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Lin, Jia-Ren, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Erin McCarty, et al. "Abstract A028: Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images." Cancer Research 82, no. 23_Supplement_1 (December 1, 2022): A028. http://dx.doi.org/10.1158/1538-7445.crc22-a028.
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Abstract Histopathology using Hematoxylin and Eosin (H&E) stained tissue sections plays a central role in the diagnosis and staging of diseases. The transition to digital H&E pathology affords an opportunity for integration with recently developed, highly multiplexed tissue imaging methods. Here we describe an approach (and instrument) for collecting and analyzing H&E and high-plex immunofluorescence (IF) images from the same cells at subcellular-resolution in a whole-slide format suitable for translational and clinical research and eventual deployment in a diagnostic setting. IF and H&E images provide highly complementary information for analysis by human experts and machine learning algorithms. Using images of 40 human colorectal cancer resections, we demonstrate the automated generation and ranking of computational models, based either on immune infiltration or tumor-intrinsic features, that are highly predictive of progression-free survival. When these models are combined, a hazard ratio of ~0.045 can be achieved, suggesting the potential of integrated H&E and high-plex imaging in the generation of high performance prognostic biomarkers. Citation Format: Jia-Ren Lin, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Erin McCarty, Keith L. Ligon, Steven Reese, Tad George, Sandro Santagata, Peter Sorger. Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A028.
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Hixson, Walter L. "Through the History of the Cold War: The Correspondence of George F. Kennan and John Lukacs. Edited by John Lukacs. (Philadelphia, Pa.: University of Pennsylvania Press, 2010. Pp. xii, 276. $39.95.)." Historian 73, no. 4 (December 1, 2011): 832–33. http://dx.doi.org/10.1111/j.1540-6563.2011.00308_26.x.
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Curtis Jr, James E. "Economic History and Philosophy, Summaries of the Autumn 2018-Spring 2019 WAEHS." Journal of Research in Philosophy and History 3, no. 1 (February 5, 2020): p1. http://dx.doi.org/10.22158/jrph.v3n1p1.
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Curtis Jr (2018) provides exhibits from January 4-7, 2018 American Economic Association, in coordination with the Allied Social Sciences Association Conference, in Philadelphia, PA, witb four tables describing i. a dictionary of higher education research products, ii. applied research conference and journal publication systems, and iii. empirical labor market studies. Curtis Jr (2019) provides summaries from the 2018-2019 Washington Area Economic History Seminar, WAEHS, hosted by American University, Washington DC USA, and George Mason University, Arlington VA USA, with three exhibits for each of the four seminars, i. the flyer from American University Department of Economics, ii. the paper abstracts from author’s and presenters, with the theme of Economic History, from presenters invited from colleges and universities throughout the USA, and iii. the seminar summaries of Curtis Jr (2019), using a research archivist sequence of information. Contributions of Curtis Jr (2019) include I. a brief history of four philosophers, II. the economic demography of US political parties, III. an asymmetry hypothesis in labor market interventions, where high skilled labor are sub-grouped disenfranchised, and IV. a restatement of the political economy modes of production. The attendees of the history seminar included, i. college/university faculty, ii. federal government economic researchers, and iii. private sector economic history researchers. Curtis Jr (2019) divided the presentation of this paper into 5 sections, (1) an introduction to the history of the theory of knowledge, i.e., Philosophy, of collegiate topics, i.e., economic history, (2) comparisons to the Economic History Association and WAEHS exhibits, (3) Research Observations by Curtis Jr (2019), (4) Results and Conclusion, and (5) Research References.
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Abo, Muthana Al, Daniel J. George, Steven R. Patierno, and Jennifer A. Freedman. "Abstract C053: Differences in hallmark gene sets in the Molecular Signatures Database between tumors from African American and White patients." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C053. http://dx.doi.org/10.1158/1538-7755.disp22-c053.
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Abstract To improve cancer outcomes, it is of critical importance to understand biological differences in tumors that ultimately accompany progression to a lethal phenotype. Compared to Whites (Ws), African Americans (AAs) suffer from higher mortality rates for some cancer types, such as prostate and breast cancer. The etiology for these cancer disparities includes an array of attributes related to societal, social, lifestyle, environmental, access and individual, ancestry-related differences. A combination of these etiologies can lead to differences in cancer biology and, therefore, differences in mortality. Differential regulation of various cancer-related pathways in tumor cells can contribute to differential mortality and morbidity outcomes, and influence cancer response to treatment. Therefore, we performed pathway analysis using publicly available gene expression datasets to compare the variation in established cancer-related pathways between tumors from AA and W patients. Molecular Signatures Database (MSigDB) is a widely used database to perform gene enrichment analysis in cancer biology. Using The Cancer Genome Atlas (TCGA) datasets from 18 tumor types and the Gene Set Variation Analysis (GSVA) method, we interrogated MSigDB hallmark gene sets between tumors from AAs and Ws. By comparing the gene set variations in tumors between AAs and Ws, we identified gene sets exhibiting significant (|∆ Z-score| > 2 and p < 0.05) variation by race. For example, our analysis revealed that the variation of 1) MYC targets increases in breast, colon, and uterine cancer from AAs compared to Ws, 2) G2M checkpoint and E2F targets increase in breast and uterine cancer from AAs compared to Ws, and 3) interferon gamma and alpha response and allograft rejection increase in renal clear cell carcinoma from AAs compared to Ws. We also performed survival analysis to identify the MSigDB hallmark gene sets whose variation scores exhibit differential association with overall survival among AA and W patients. Among the gene sets associated differentially by race with overall survival are MYC targets in breast cancer and PI3K AKT MTOR signaling in colon cancer; with variation exhibiting an association with higher overall survival among AA patients compared with W patients. Thus, our analysis reveals how the widely accepted MSigDB hallmark gene sets differ between tumors from AAs and Ws and differentially associate with survival among AA and W patients. The majority of published studies reporting pathways relevant to cancer biology have been based on data from W patients. Therefore, evaluation of hallmark gene sets in cancers from diverse patients has important implications for understanding cancer biology and developing precision medicine interventions. Citation Format: Muthana Al Abo, Daniel J. George, Steven R. Patierno, Jennifer A. Freedman. Differences in hallmark gene sets in the Molecular Signatures Database between tumors from African American and White patients [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C053.
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Scarton, Lisa, Ara Jo, Zhigang Xie, LaToya J. O’Neal, Juan M. Pena, Thomas J. George, and Jiang Bian. "Abstract 502: The association of metformin dose and cancer survival in older adults with advanced cancer: SEER-Medicare analysis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 502. http://dx.doi.org/10.1158/1538-7445.am2022-502.
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Abstract Cancer and type 2 diabetes (T2DM) are common diseases that have serious health consequences. T2DM is known to increase the risk for the development of many of the most common cancers. Metformin, one of the most commonly used drugs to treat T2DM, is increasingly being used for its anticancer effects; however, the literature is limited on the effect of metformin dose on OS in patients with advanced cancer. We examined the relationship between metformin dose and OS in persons with both T2DM and stage IV lung, breast, colorectal, prostate, or pancreas cancers. Methods: We used a retrospective study design with cox proportional hazards regression analysis of the 2007-2016 of the Surveillance Epidemiology and End Results-Medicare dataset. Results: A total of 7,725 patients with T2DM and a least one targeted cancer was included in the analysis. Of those patients, 38.5% had been prescribed metformin. Patients who used metformin had significantly better OS in both unadjusted (Unadjusted HR, 0.73; 95% CI, 0.69-0.76; p < 0.001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73-0.81; p < 0.001). The OS between patients who took metformin with average daily dose ≥ 1000mg or < 1000mg were not statistically significant (aHR, 1.00; 95% CI, 0.93-1.08; p=0.90). Conclusions: Metformin use, regardless of dose, increases OS in older adults with advanced cancer. Additionally, OS was not significantly different across race or ethnicity. Citation Format: Lisa Scarton, Ara Jo, Zhigang Xie, LaToya J. O’Neal, Juan M. Pena, Thomas J. George, Jiang Bian. The association of metformin dose and cancer survival in older adults with advanced cancer: SEER-Medicare analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 502.
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Kleffman, Kevin, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, et al. "Abstract LB052: Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB052. http://dx.doi.org/10.1158/1538-7445.am2022-lb052.
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Abstract Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Aβ decreases brain metastatic burden. Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer’s disease - two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. Citation Format: Kevin Kleffman, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von-Itter, Alfredo Floristán, Gillian Baptiste, Nicole Eskow, James Tranos, Jenny Chen, Eleazar C. Vega Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue Ming Li, Paul Mathews, Ronald Demattos, Beatrix Ueberheide, Kelly Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando. Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB052.
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Shaji, Sherin George, Pratikkumar Patel, and Kun Cheng. "Abstract 384: Lipid nanoparticle aided delivery of a STING agonist to treat pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 384. http://dx.doi.org/10.1158/1538-7445.am2022-384.
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Abstract The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a huge population of cancer-associated fibroblasts, myeloid-derived suppressor cells, regulatory T cells, and a scarce number of effector immune cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. Agonists of STING have been shown to inflame the TME, reduce tumor burden and confer anti-tumor activity in mouse models. 2’, 3’ cyclic guanosine monophosphate adenosine monophosphate (cGAMP) is a high-affinity endogenous ligand of STING. However, the cytosolic delivery of exogenous cGAMP to antigen-presenting cells and tumor cells remains a challenge due to poor cellular permeability, poor stability, and rapid clearance. We address these limitations by encapsulating cGAMP in a lipid nanoparticle (cGAMP-LNP) engineered for efficient cytosolic delivery. The size and morphology of the cGAMP-LNP were characterized using dynamic light scattering and TEM, respectively. The in-vitro activity of the cGAMP-LNP was determined in the THP-1 Blue࣪ ISG reporter cell line, whereas the endosomolytic activity of the LNP was evaluated by red blood cell hemolysis assay. The cGAMP-LNP activates the IRF3 pathway in-vitro and shows concentration- and pH-dependent endosomolytic activity. Moreover, the cGAMP-LNP was evaluated for cytotoxicity in-vitro and were found non-toxic to human pancreatic duct epithelial cell line at bioactive concentrations. Collectively, the cGAMP-LNP represents a promising strategy to convert immunosuppressive pancreatic cancer to immune-inflamed pancreatic cancer. Citation Format: Sherin George Shaji, Pratikkumar Patel, Kun Cheng. Lipid nanoparticle aided delivery of a STING agonist to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 384.
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Moran, Amy E., Fanny Polesso, Zheng Xia, George Thomas, and Julie Graff. "Abstract 1301: T cell intrinsic androgen receptor activity regulates response to immunotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1301. http://dx.doi.org/10.1158/1538-7445.am2022-1301.
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Abstract Immune checkpoint blockade has revolutionized the field of oncology inducing durable anti-tumor immunity in many solid tumors. In advanced prostate cancer patients, immunotherapy treatments have largely failed. Androgens have pleiotropic functions in prostate cancer; they are potent drivers of cancer cell growth and can suppress T cell function. In metastatic prostate cancer, intratumor androgen levels can remain high. Androgen deprivation therapy, the backbone of clinical care in prostate cancer, is classically administered to inhibit tumor cell growth. We postulated that this therapy also impacts tumor associated T cells. To test this hypothesis, we performed transcriptome profiling of individual leukocytes isolated from metastatic prostate cancer lesions resistant to androgen deprivation therapy (ADT) and androgen receptor (AR) antagonism and prior to treatment with a PD-1 inhibitor. We reveal that inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. Notably, AR directly bound to Ifng and eviction of this transcription factor with a small molecule significantly increased cytokine production in CD8 T cells. Furthermore, genomic deletion of Ar prevented chronically stimulated CD8 T cells from losing their ability to make IFNγ upon restimulation. Finally, we demonstrate that AR blockade sensitizes multiple tumor mouse models to effective checkpoint blockade by directly enhancing CD8 T cell function. Together, our findings establish T cell specific AR activity as one mechanism of immunotherapy resistance and show that targeting AR can improve immunotherapy outcomes. Citation Format: Amy E. Moran, Fanny Polesso, Zheng Xia, George Thomas, Julie Graff. T cell intrinsic androgen receptor activity regulates response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1301.
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Jenkins, Laura J., Ian Y. Luk, Walter D. Fairlie, Erinna F. Lee, Michelle Palmieri, Kael L. Schoffer, Tao Tan, et al. "Abstract B014: Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death." Cancer Research 82, no. 23_Supplement_1 (December 1, 2022): B014. http://dx.doi.org/10.1158/1538-7445.crc22-b014.
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Abstract The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumor organoids in vitro,and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only pro-apoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in CRCs, by combining a HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT ; KRASG12C , BRAFV600E CRC cell lines respectively. These findings identify a series of ERK/MAPK genotype tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer. Citation Format: Laura J. Jenkins, Ian Y. Luk, Walter D. Fairlie, Erinna F. Lee, Michelle Palmieri, Kael L. Schoffer, Tao Tan, Irvin Ng, Natalia Vukelic, Sharon Tran, Janson Tse, Rebecca Nightingale, Zakia Alam, Fiona Chionh, George Iatropoulos, Matthias Ernst, Shoukat Afshar-Sterle, Jayesh Desai, Peter Gibbs, Oliver M. Sieber, Amardeep S. Dhillon, Niall C. Tebbutt, John M. Mariadason. Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B014.
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Taylor, Renee, and Andrea Silber. "Abstract B091: Introduction of Implicit Bias Training to oncology faculty as a means to improve minority participation in cancer clinical trials." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): B091. http://dx.doi.org/10.1158/1538-7755.disp22-b091.
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Abstract Background: Following George Floyd’s murder in May 2020, conversations about equity and bias became part of our daily national conversation. Simultaneously the COVID-19 outbreak disproportionately affected people of color which further illuminated existing disparities in outcomes. Bias training was introduced in many sectors as a strategy to address inequity. Inclusivity in healthcare is essential to develop evidence-based therapies and treatment plans. Previous studies have demonstrated the consequences when racial and ethnic minorities are excluded from research. (Hamel et al, 2016). Racial and ethnic minorities disproportionately bear adverse outcomes from cancer. Cancer clinical trials would benefit from solutions to promote inclusivity. (Khan et al. 2021) Research Purpose: The purpose of our study was to assess whether Implicit Bias Training can increase minority participation in cancer clinical trials. Methodology: The Office of Diversity, Equity, and Inclusion offered Implicit Bias Training to all clinical oncologists at the Yale Cancer Center (YCC) between May and July 2021. While 109 physicians were eligible to participate, 57 physicians were required by the department to complete this training, and 84% of these physicians completed this opportunity. We analyzed YCC clinical trial enrollment data between two time periods defined as pre-intervention and post-intervention. We selected these periods to investigate not only the efficacy of bias training but specifically bias training as an adjunct to the national conversation during the time of our study. We selected the preintervention period as January 1, 2021, to June 30, 2021. The intervention was designed to be completed by July 1, 2021 therefore the post-intervention period is defined as July 1, 2021 to December 31, 2021. Results/Summary: Our analysis showed an increase of 2.5% in the participation of Black/African American patients. There was a slight (1.5%) decrease in Hispanic patient enrollment during this time. Conclusion: Our analysis suggested that implicit bias training delivered once had only a very modest, if any, improvement in racial minority participation in cancer clinical trials. Our project focused on participation by Black/African American patients. The impediment to Hispanic participation is quite nuanced. Hispanic patients, many of whom are non-English speaking with immigration/insurance issues face additional structural barriers. We think that a different strategy is needed to better serve this patient population. While we had hoped for metrics to demonstrate greater impact from bias training, our next investigation will look at if the intervention is best delivered repeatedly. Future Work: We have not abandoned the strategy of bias training to build trust and increase Black/AA participation. After the intervention, we are interested in whether greater impact is seen over time. We have designed a survey to look at the effects of the intervention after a year. Our next step is to examine whether repeated delivery of this intervention will amplify our results. Citation Format: Renee Taylor, Andrea Silber. Introduction of Implicit Bias Training to oncology faculty as a means to improve minority participation in cancer clinical trials [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B091.
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Scarton, Lisa, Tarah Nelson, Yingwei Yao, Shavondra Huggins, Ara Jo, LaToya J. O'Neal, Thomas J. George, et al. "Abstract B130: Feasibility metric outcomes: A nurse-led intervention to identify and manage undiagnosed type 2 diabetes in patients with newly diagnosed cancer." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): B130. http://dx.doi.org/10.1158/1538-7755.disp22-b130.
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Abstract Background: Each year 1.4 million adults are diagnosed with diabetes, and in 2022 more than 1.9 million Americans will be diagnosed with cancer. There is a strong link between type 2 diabetes (T2D) and several types of cancer, and both conditions are known for health disparities. Unrecognized or poorly managed T2D is associated with higher staged cancer at diagnosis and cancer mortality rates with reduced overall survival. Yet, it is not standard oncology practice to test newly diagnosed cancer patients for T2D. Nurses are well positioned to facilitate testing and management of T2D.Aim: The purpose of this study was to examine the feasibility of a nurse-led intervention for adults with newly diagnosed cancer and undiagnosed T2D.Method: In a randomized feasibility pilot study conducted within a large academic medical oncology center, we used EPIC to identify adults with newly diagnosed cancer (< 3 months). The intervention group received immediate initiation of metformin and T2D management education. The standard care group received referral back to their primary care provider. The study measures included HbA1c and feasibility metrics (i.e., population availability, recruitment efficiency and sample retention).Results: Two days a week, over an 11-month timeframe, we pre-screened 379 adults (78.4% non-Hispanic White, 12.9% Black, 1.6% Asian, .5% American Indian, 7.1% other) for study eligibility. Of those pre-screened only 55 (14.5%) patients were eligible for HbA1c screening. The rest were excluded due to current use of metformin (16%), abnormal labs (AST/ALT, eGFR) (16%), or poor prognosis (e.g., pancreatic cancer or leukemia; 18%). Of the 55 patients screened, one non-Hispanic White man, one non-Hispanic White woman, and one Black woman met HbA1c ≥ 6.5% eligibility for the intervention (mean age 58.3, two patients had breast cancer and one patient had rectal cancer); one patient was randomized to the intervention group and two patients were randomized to the standard care group. The initial HbA1c for the intervention group patient was 6.7% and decreased to 5.1% after 3 months (primary endpoint). For the two standard care group patients, the HbA1c was 7.2% and 6.7% and decreased to 5.5%, 5.9%, respectively, after 3 months. No patients were lost to follow-up. All three patients indicated that they enjoyed participating in the study, the length of the study was good, and felt the study would be well received by other patients. The study was subsequently closed due to failing feasibility metrics. Conclusion: Despite study acceptability to patient, this T2D screening protocol was deemed not feasible due to recruitment inefficiency including cost, time, and personnel to screen at the point of care. Integrating routine HbA1c tests for all newly diagnosed cancer patients would simplify screening for study, which would allow another feasibility study of a promising intervention to improve management of undiagnosed T2D among newly diagnosed patients with cancer. Citation Format: Lisa Scarton, Tarah Nelson, Yingwei Yao, Shavondra Huggins, Ara Jo, LaToya J. O'Neal, Thomas J. George, Juan M. Munoz-Pena, Merry J. Markham, Martina C. Murphy, Jonathan A. Chatzkel, Sherise Rogers. Feasibility metric outcomes: A nurse-led intervention to identify and manage undiagnosed type 2 diabetes in patients with newly diagnosed cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B130.
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Holt, Hunter K., Caryn Peterson, Shannon MacLaughlan, George F. Sawaya, and Gregory S. Calip. "Abstract A091: Mediation of racial/ethnic inequities in the diagnosis of early-stage cervical cancer by insurance status." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): A091. http://dx.doi.org/10.1158/1538-7755.disp22-a091.
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Abstract Background: Black and Latina/Hispanic women are more likely to be diagnosed with and die from cervical cancer than White women in the US. Having adequate health insurance, a social and structural determinant of health, may be associated with an earlier stage cervical cancer diagnosis and improved prognosis for racial/ethnic minorities. Objective: To determine whether insurance status among racial/ethnic groups is associated with earlier diagnosis of cervical cancer among a large and diverse population of US women with cervical cancer. Methods: A retrospective, cross-sectional population-based study utilizing data from the Surveillance, Epidemiology, and End Results Census Tract-Level Socioeconomic Status and Rurality Database on 24,945 women aged 21-64 years who were diagnosed with a histologically confirmed invasive cervical cancer between January 1, 2007, to December 31, 2016. The primary outcome was the risk of having a more advanced cervical cancer diagnosis (regional or distant versus localized). Causal mediation analyses were performed using a series of multivariable logistic regression models to determine the association of race/ethnicity with cervical cancer stage and the potential mediator, health insurance status (private insurance versus Medicaid coverage or no insurance). Adjusted odds ratios (OR) and 95% confidence intervals were calculated, and estimates of direct and indirect effects of race/ethnicity and cervical cancer stage were used to calculate the proportion mediated (PM) by health insurance status. Results: 24,945 women (median [IQR] age, 45 [37-54] years) were included in the study. 52% of women were identified as Non-Hispanic (NH) White, 13% as NH Black, and 24% as Hispanic/Latina. Overall, 14,271 women had private insurance, 9,765 women were uninsured or received Medicaid, and 909 women had no documented insurance status. A larger proportion of women who were uninsured or received Medicaid were diagnosed with more advanced stage cancer (regional/distant) compared to women with private health insurance (53.5% versus 42.0%). In models adjusted for age, year of diagnosis and histology type: NH Black (OR 1.38, 95% CI 1.27-1.50), and Hispanic/Latina (OR 1.13, 95% CI 1.06-1.21) women had higher odds of being diagnosed with regional/distant cancer compared to NH White women. After adjustment for insurance status and accounting for co-mediation by area-level socioeconomic status, the association with regional/distant cervical cancer was attenuated toward the null (Black: OR 1.18, 95% CI 1.08-1.29; Hispanic/Latina: OR 0.93, 95% CI 0.87-1.00). Our mediation analysis found that over half (PM 51% to 56%) of the inequities in cervical cancer diagnosis were mediated by health insurance across all racial/ethnic groups. Conclusion: In this population-based sample of US women, insurance status was major mediator of over half the racial/ethnic inequities in late-stage cervical cancer diagnoses. Focused policies making robust health coverage accessible may mitigate the known inequities in cervical cancer diagnosis and outcomes. Citation Format: Hunter K. Holt, Caryn Peterson, Shannon MacLaughlan, George F. Sawaya, Gregory S. Calip. Mediation of racial/ethnic inequities in the diagnosis of early-stage cervical cancer by insurance status [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A091.
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Arnst, Jamie, and George Beck. "Abstract 2408: Elevated phosphate promotes a pro-migration phenotype in lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2408. http://dx.doi.org/10.1158/1538-7445.am2022-2408.
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Abstract Despite advances in treatment, metastasis remains a major cause of cancer-associated death in the US. Thus, identification of intrinsic and extrinsic factors that promote or inhibit tumor migration and invasion are critical. Increasingly, the dysregulation of cellular metabolism is being linked not only to tumor growth but tumor cell migration. Phosphorus (Pi) is an essential micronutrient necessary for energy metabolism, cell signaling via ATP, formation of nucleic acids and the cell membrane, and mineralization of the skeleton. Unsurprisingly, high levels of Pi are observed in tumor tissue compared to normal tissue, consistent with a demand for this metabolite in rapidly growing cells. Further, our lab has reported that high extracellular Pi increases cell growth, alters gene expression and protein translation, and promotes angiogenesis. High dietary Pi levels has also been shown to increase tumorigenesis in both lung and skin cancer models. However, it remains unknown how phosphate metabolism affects tumor migration and invasion. Here we report that high levels of Pi increases gene expression of EMT-related genes such as Twist, Vimentin, CD44, and OPN in the lung cancer cell line, A549. Further, increased Pi promotes tumor cell migration in a transwell assay and decreased Pi levels or inhibition of phosphate transport by phosphonoformic acid (PFA) impaired migration. Suggesting that high Pi can promote a pro-migration phenotype by upregulating EMT in cancer cells and by increasing directed cell migration. Ongoing research will focus on how intracellular Pi flux changes during cell invasion using a novel FRET-based phosphate sensor in vitro and the effect of Pi inhibition on metastasis in vivo. These findings provide further evidence for the role dysregulated Pi metabolism in promoting cancer progression and the potential for therapeutic intervention with broad impacts on patient outcomes. Citation Format: Jamie Arnst, George Beck. Elevated phosphate promotes a pro-migration phenotype in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2408.
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Bei, Yi, Marieluise Kirchner, Luca Brame, Raphaela Fritsche-Guenther, Julia Koeppke, Anja Heeren-Hagemann, Philipp Mertins, Jan Dörr, and Anton George Henssen. "Abstract 1882: Passenger gene co-amplification leads to collateral vulnerabilities in cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1882. http://dx.doi.org/10.1158/1538-7445.am2022-1882.
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Abstract The activation of oncogenes via genomic amplification is a hallmark of the cancer genomes, yet such amplifications frequently also encompass neighboring genes. Such passenger genes are involved in essential cellular activities. We hypothesized that co-amplification of passenger genes create cancer-specific collateral therapeutic vulnerabilities. To test this, we analyzed one of the most commonly amplified gene locus near MYCN, which is amplified in nearly 25% of neuroblastoma and around 5% of all cancers. We observed that DDX1, a DEAD-Box helicase, is the most frequently co-amplified passenger gene in MYCN-amplified cancers. Using CRISPR/Cas9 loss-of-function screen results from the Cancer Dependency Map across 739 human cancer cell lines, we reveal that cells with DDX1 co-amplification are highly dependent on the mTOR complex 1(mTORC1). Mechanistically, western blot and immunoprecipitation analyses shows that DDX1 expression leads to higher mTORC1 pathway activity through the interaction between DDX1 and alpha-ketoglutarate dehydrogenase(alpha-KGDH) in mitochondria. DDX1 hijacks alpha-KGDH complex, thereby impairing the function of the Krebs cycle by interfering with the conversion of alpha-ketoglutarate to succinyl-coA. Live cell metabolomics shows accumulated alpha-ketoglutarate in turn activates mTORC1 pathway to promote the ATP production via oxidative phosphorylation(OXPHOS) to maintain cell survival. Consequently, interference with mTORC1 function reduced ATP production and led to accumulated alpha-KG leading to cell death, specifically in DDX1 expressing cells. This suggests that co-amplification of a passenger gene can result in collateral vulnerabilities in cancers, which has the potential to transform future therapeutic target discovery in oncology. Citation Format: Yi Bei, Marieluise Kirchner, Luca Brame, Raphaela Fritsche-Guenther, Julia Koeppke, Anja Heeren-Hagemann, Philipp Mertins, Jan Dörr, Anton George Henssen. Passenger gene co-amplification leads to collateral vulnerabilities in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1882.
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Wang, Yiyun, Xiangjun He, Linqin Wang, Mi Shao, Yanan Yue, Yangbin Gao, George Church, He Huang, and Luhan Yang. "Abstract 3155: "Super NK cells" - natural killer cells derived from engineered hiPSC with enhanced NK receptor expression demonstrate better anti-tumor effects for solid tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3155. http://dx.doi.org/10.1158/1538-7445.am2022-3155.
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Abstract CAR-T cells expressing chimeric antigen receptors (CAR) have shown clinical success for treating hematologic malignancies, but their efficacy in solid tumors has been limited, largely due to tumor heterogeneity and immunosuppressive tumor microenvironment (TME). Natural Killer (NK) cells derived from human induced pluripotent stem cells (hiPSC) hold great potential to become the next-generation cell therapy products because of their established safety profile and their unique biological activities, especially their potential effectiveness for targeting solid tumor. In contrast to T cells, NK cells exert anti-tumor activity without requiring antigen recognition through MHC complex; they are instead activated by calculated signaling through ligation of multiple activating and inhibitory receptors. As various solid tumors highly express activation ligands for NK cells, we reason that enhanced expression of activation receptors on NK cells could improve their killing activity towards solid tumors. Here, we report that “super NK cells” with more than 10 folds higher expression of NK cell receptors such as NKG2D and NCRs derived from engineered hiPSC show improved cytotoxicity against solid tumors compared with non-engineered ones. The “super NK cells” can achieve more than ten rounds of serial killing against both K562 and THP-1 cell lines in vitro. More importantly, the “super NK cells” show improved cytotoxicity to multiple solid tumors in both in vitro system and in vivo xenograft mouse models. In summary, we have engineered hiPSCs which can be differentiated into "super NK cells" as a potential cell therapy product for improved efficacy against solid tumors. Citation Format: Yiyun Wang, Xiangjun He, Linqin Wang, Mi Shao, Yanan Yue, Yangbin Gao, George Church, He Huang, Luhan Yang. "Super NK cells" - natural killer cells derived from engineered hiPSC with enhanced NK receptor expression demonstrate better anti-tumor effects for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3155.
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Emamzaden, Fatemeh Nouri, Beverly Word, George Hammons, and Beverly D. Lyn-Cook. "Abstract 1631: Anti-cancer effects of vorinostat on 3D cultured pancreatic cancer cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1631. http://dx.doi.org/10.1158/1538-7445.am2022-1631.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, often having a low survival rate mainly due to late diagnosis and limited therapies because of drug resistance. Treatment results shown in cell models used in studying various drugs often fail in clinical trials. The lack of translation of the effects observed in vitro to patients continues to halt progress. Genetic mutations are known in PDAC; however, recent studies have suggested the role of epigenetics in its initiation and progression to a malignant phenotype. Histone deacetylase (HDAC) proteins are highly expressed in a variety of cancers, including pancreatic cancer. Recent studies have shown that targeting these proteins through the use of HDAC inhibitors may be an effective therapy for pancreatic cancer. Using a 3D cultured pancreatic cell model, anti-cancer effects by vorinostat, a HDAC inhibitor, were investigated. Although both pancreatic cell lines, PANC-1 and Mia, contain mutated K-ras and P53, a differential effect in response to vorinostat was observed in expression of cancer genes using a Human Pancreatic Adenocarcinoma TagMan Array 96 (Applied Biosystems). In the PANC-1 cell model, vorinostat decreased expression of STAT6, which is known to play a role in migration and invasion. It also decreased significantly expression of insulin growth factor 1 (IGF1), IL-6, EGF, VEGFA and TGFB1. CCND2 and CCND2 were also downregulated. In contrast, Mia cell model showed decreased expression of EGF and IGF1, but no change with the other genes. These data suggest that vorinostat has effects on several potential pathways in pancreatic cancer possibly through epigenetic mechanisms that affect certain genes involved in progression and invasion. Currently, this drug in combination with other drugs is being investigated for pancreatic cancer. Citation Format: Fatemeh Nouri Emamzaden, Beverly Word, George Hammons, Beverly D. Lyn-Cook. Anti-cancer effects of vorinostat on 3D cultured pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1631.
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Rosenberg, Martin, Jennifer R. Bethard, Linda Aronoff, and George Lipkin. "Abstract A31: A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype." Cancer Research 80, no. 19_Supplement (October 1, 2020): A31. http://dx.doi.org/10.1158/1538-7445.mel2019-a31.
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Abstract Knowledge of the molecular basis for contact inhibition of growth, an in vitro property differentiating benign from malignant cells and correlated with in vivo growth control, could provide new targets for reestablishing control of malignant cell proliferation. We previously reported a soluble Contact Inhibitory Factor (CIF) in culture medium from a revertant contact inhibited melanoma cell line that restored contact-, serum-, and anchorage-dependent growth control to melanoma cells, closely linked to reversal of multiple malignant properties and whose contact inhibitory effects extended to a wide spectrum of other cancers. We now report identification, purification, and synthesis of the molecule, CIF, responsible for restoring contact inhibition: a structurally novel cyclic decapeptide dimer. Its discovery has both clinical and theoretical implications. Availability of CIF should not only facilitate evaluation of its therapeutic potential but also may provide the key to its target and the sequence of molecular events linking contact inhibition to broad phenotypic reversal. CIF may be the ligand for a widely distributed contact inhibitory checkpoint, one that is defective in cancer cells but pharmacologically correctible by CIF, and controlling replication at a single locus, potentially simplifying treatment. CIF is the first cell-derived peptide that restores contact inhibition of growth to melanoma and a wide spectrum of other cancers, with an obligatory link in melanoma to reversal of multiple aspects of the malignant phenotype. It suggests the possibility of an alternative approach to treatment of intractable melanoma and other cancers: broad-spectrum, endogenous peptide-based control of malignancy through phenotypic reversal that tilts the biologic balance to favor host recapture of control over tumor. Citation Format: Martin Rosenberg, Jennifer R. Bethard, Linda Aronoff, George Lipkin. A novel melanoma-derived cyclic decapeptide dimer mediates restoration of contact inhibition of growth and reversal of the malignant phenotype [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A31.
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Zaman, Saif, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, and George Blanck. "Abstract B12: Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma." Cancer Research 80, no. 19_Supplement (October 1, 2020): B12. http://dx.doi.org/10.1158/1538-7445.mel2019-b12.
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Abstract Introduction: Proteases in the cancer microenvironment have been studied for decades, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regrading that conclusion in later stages of cancer development. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of the cancer microenvironment has become available. Methods: To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of ECM structural proteins, on MMP2, a protease extensively associated with melanoma in terms of both protease sensitivity and MHC class I binding using original software. Additionally, T-cell receptor TRα and TRβ recombinations were bioinformatically obtained using whole-exome sequencing data from 479 melanoma tumor samples. Results: Tumor samples with mutant amino acids adjacent to ECM structural protein, MMP2-cleavage sites represented a better survival rate and a larger proportion of mutant peptides with high HLA class I binding affinities, particularly in comparison to melanoma samples lacking a T-cell infiltrate. Furthermore, even better MHC class I binders, as a group, were identified among the sample representing ECM structural proteins mutants not adjacent to MMP2 sensitive sites and evincing a relatively poor survival rate. Conclusion: Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an antitumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression. Citation Format: Saif Zaman, Boris I. Chobrutskiy, Jay S. Patel, Blake M. Callahan, Moody Mihyu, Andrea Diviney, Wei Lue Tong, George Blanck. Potential neoantigen release and increased lymphocyte activity is facilitated by matrix metalloproteinase-dependent cleavage of mutant matrisome peptides in cutaneous melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B12.
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Lin, Anthony, Jennifer Feng, Xiang Chen, Dunrui Wang, Megan Wong, George Zhang, Joseph Na, et al. "Abstract PO-060: N-terminal RHAMM cooperates with dysfunctional p53 to accelerate the progression of pancreatic cancer." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—060—PO—060. http://dx.doi.org/10.1158/1538-7445.panca21-po-060.
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Abstract Pancreatic cancer has the lowest survival rate in all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages. A better therapeutic development for this devastating disease is urgently needed. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm−/− mice. However, we found that Rhamm−/− mice expressed a N-terminal RHAMM protein. While N-terminal RHAMM did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of N-terminal RHAMM was not apparent in these mice with short life span. In addition, N-terminal RHAMM shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, N-terminal RHAMM that lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC) accelerated pancreatic cancer progression. Citation Format: Anthony Lin, Jennifer Feng, Xiang Chen, Dunrui Wang, Megan Wong, George Zhang, Joseph Na, Tiantian Zhang, Zhengming Chen, Yao-Tseng Chen, Yi-Chieh Nancy Du. N-terminal RHAMM cooperates with dysfunctional p53 to accelerate the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-060.
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Schaefer, Inga-Marie, Matthew L. Hemming, Meijun Z. Lundberg, Matthew P. Serrata, Isabel Goldaracena, Ninning Liu, Peng Yin, et al. "Abstract A013: CDK2 and CDK4/6 inhibition in GIST: Mechanisms of response and resistance." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): A013. http://dx.doi.org/10.1158/1557-3265.sarcomas22-a013.
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Abstract Advanced GIST is characterized by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor (CDK4/6i) therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximizing response to therapeutic CDK4/6 inhibition. Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples (N=18), including 8 metastatic TKI-resistant GISTs. Multiple metastases were analyzed in 3 patients. The impact of CDK2i (CDK2 inhibitor-II), CDK4/6i (palbociclib or abemaciclib), and CDK2/4/6i (PF-06873600) was determined through cell proliferation and protein detection assays in vitro and in vivo. Mechanisms of acquired CDK2i and CDK4/6i resistance were characterized in GIST cell lines after long-term exposure. The results demonstrate recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways. Identical aberrations of p16, RB1, and TP53 were present in all metastases from 3 patients. We show that therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation (P<0.01). Intact RB1 predicted response to treatment, whereas RB1-deficient models were resistant. Moreover, we identify RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) as mechanisms of acquired CDK inhibitor resistance in GIST. The CCND1 rearrangement deleted the cyclin D1 C-terminal Thr286 and Thr288 residues which mediate cyclin D1 proteasomal degradation, resulting in overexpression of an abnormal cyclin D1. CDK inhibitor resistance properties were corroborated by lentiviral transduction of the CCND1 fusion gene into fusion-negative GIST, leiomyosarcoma, and breast cancer cells. These studies establish the biologic rationale for CDK2 and CDK4/6 co-inhibition as therapeutic strategy in patients with advanced GIST, including patients with metastatic GIST progressing on TKIs. In addition, these findings expand the spectrum of potential CDK inhibitor resistance mechanisms with translational potential for improving cell cycle targeted therapies in other cancer types. Citation Format: Inga-Marie Schaefer, Matthew L. Hemming, Meijun Z. Lundberg, Matthew P. Serrata, Isabel Goldaracena, Ninning Liu, Peng Yin, Joao A. Paulo, Steven P. Gygi, Suzanne George, Jeffrey A. Morgan, Monica M. Bertagnolli, Ewa T. Sicinska, Adrian Mariño-Enríquez, Jason L. Hornick, Chandrajit P. Raut, George D. Demetri, Wen-Bin Ou, Sinem K. Saka, Jonathan A. Fletcher. CDK2 and CDK4/6 inhibition in GIST: Mechanisms of response and resistance [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A013.
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Hu, Jennifer J., Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, and Eunkyung Lee. "Abstract 2328: Metabolomics pathways and biomarkers in predicting breast cancer prognosis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2328. http://dx.doi.org/10.1158/1538-7445.am2022-2328.
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Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in Americans. With more than 3 million breast cancer survivors in the US, a number that is projected to increase, it is important to identify targets for precision intervention to improve breast cancer prognosis. With the rapid advancement of technology for metabolomics, the results from several recent studies have shown that metabolomics may have applications in breast cancer diagnosis and subtype analysis, characterization of heterogeneity of breast cancer, and prognosis. In the current study, we performed a global urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) cases as the reference group and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). The urine samples were collected immediately after radiotherapy. Using UPLC-MS/MS and GC-MS, Metabolon Inc. identified a robust set of 1,742 biochemicals (1,258 known and 484 unknown structure). The most notable differences between PF and PD patients involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., glucose, sedoheptulose, and N6-carboxymethyllysine), branch-chain amino acid metabolism (e.g., alpha-hydroxyisocaproate and beta-hydroxyisovalerylglycine), phosphatidylcholine metabolism (e.g., 1-palmitoyl-2-oleoyl-GPC (16:0/18:1) and 1-palmitoyl-2-linoleoyl-GPC (16:0/18:2)), arginine metabolism (e.g., dimethylarginine, N-acetylcitrulline, and homocitrulline), oxidative stress-related metabolites (e.g., cysteine-glutathione disulfide, gamma-glutamylisoleucine, and gamma-glutamylthreonine), androgenic steroids (Dehydroepiandrosterone sulfate (DHEA-S) and 16a-hydroxy DHEA 3-sulfate), and nucleotide metabolism. Some of these identified metabolomic differences may serve as potential predictive biomarkers of breast cancer prognosis. In summary, with increasing interest in targeting tumor metabolism in precision medicine and our pilot data suggesting multiple metabolic pathways in predicting breast cancer prognosis, future research is warranted to validate our findings and identify metabolomic targets for precision interventions. Citation Format: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee. Metabolomics pathways and biomarkers in predicting breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2328.
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George, Joshy, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Scott Adamson, Jong Min Choi, Brad Rybinski, et al. "Abstract 3961: Cancer stem cells, not bulk tumor cells, predict mechanisms of resistance to SMO inhibitors in SHH medulloblastoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3961. http://dx.doi.org/10.1158/1538-7445.am2022-3961.
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Abstract The emergence of primary and acquired treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Both genetic and epigenetic mechanisms of drug resistance have been reported in literature; however, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown.Here, we report that one can predict a priori the resistance mechanism that will arise in individual SMO inhibitor (SMOi)-resistant SHH medulloblastoma (MB), based on different CSC phenotypes in each tumor. We show that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway (sonic hedgehog (SHH) pathway) determines the molecular mechanism of resistance in individual tumors. Using both spontaneous (Fsmo;GFAP-cre) and transplantable (Ptch+/-;p53) mouse models of SHH MB treated with a Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only when the CSCs depend on the targeted pathway. In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs), acquire resistance through epigenetic reprogramming. Mechanistically, we discovered that the elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including the histone acetylation machinery. Consequently, SMOi-resistant SI- SMOi-resistant SI-CSC exhibit a global reduction of H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies and implicate histone acetylation in the process. This information can be clinically exploited to understand responses and resistance to SMOis and other targeted therapies. Citation Format: Joshy George, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Scott Adamson, Jong Min Choi, Brad Rybinski, Anuj Srivastava, Parveen Kumar, Min Gyu Lee, David S. Baskin, Wen Jiang, Betty Y. Kim, William Flavahan, Jeffrey H. Chuang, Sung Yun Jung, Kyuson Yun. Cancer stem cells, not bulk tumor cells, predict mechanisms of resistance to SMO inhibitors in SHH medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3961.
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Nirmal, Ajit Johnson, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce Chen, Connor Jacobson, Roxanne Pelletier, et al. "Abstract LB056: The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB056. http://dx.doi.org/10.1158/1538-7445.am2022-lb056.
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Abstract Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life-threatening when metastatic. The spatial organization of the tumor ecosystem during early-stage melanoma is not well understood. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We collected highly multiplexed single-cell data from 70 distinct histological regions from 13 specimens (patients) selected to have multiple progression-associated histologies within a single resection. These histologies range from pre-malignant fields in which melanocytic atypia represents the first steps in cancer initiation to non-invasive (radial growth phase) and invasive (vertical growth phase) primary melanoma that eventually gives rise to disseminated disease. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and primary invasive tumor. Hallmarks of immunosuppression were detectable as early as the melanoma precursor stage, and when tumors become locally invasive, a consolidated and spatially restricted environment with multiple overlapping immunosuppressive mechanisms forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1 and by PDL1-expressing macrophages and dendritic cells engaging activated T cells. However, only a few millimeters away, T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can co-exist within a few millimeters of each other in a single specimen. Multiplexed single-cell imaging and micro-region mRNA profiling link morphological and molecular features of tumor evolution within and across primary cancer specimens, revealing highly localized programs of immune and tumor cell communication via paracrine cytokine signaling and direct cell-cell contact. Citation Format: Ajit Johnson Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce Chen, Connor Jacobson, Roxanne Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger. The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB056.
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Chaturvedi, Pallavi, Varghese George, Bai Liu, Niraj Shrestha, Meng Wang, Micheal Dee, Xiaoyun Zhu, et al. "Abstract 1299: Immunotherapeutic hcw9218 enhances anti-tumor activity of chemotherapy by facilitating immune-mediated elimination of therapy induced senescent cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1299. http://dx.doi.org/10.1158/1538-7445.am2022-1299.
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Abstract Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. Here, we report a novel heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology comprising extracellular domains of the human transforming growth factor-β (TGF-β) receptor II and a human interleukin (IL)-15/IL-15 receptor α complex. This fusion complex exhibited TGF-β neutralizing activity in vitro and sequestered plasma TGF-β in vivo. Subcutaneous administration of HCW9218 was well tolerated in mice, with a half-life sufficient to provide long lasting biological activity. HCW9218 enhanced metabolic and cytotoxic activities of immune cells (CD8+ T cells, NK cells) and reduced tumor progression in models of chemotherapy induced senescence (TIS, docetaxel for B16F10 tumors and gemcitabine plus nab-paclitaxel for SW1990 tumor models) and non-TIS in vivo. Mechanistically, HCW9218 treatment not only affected the immunosuppressive tumor microenvironment but also enhanced CD8+ T cells and NK cells infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immune-depletion studies showed that HCW9218-activated NK cells played a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhanced efficacy of tumor antigen-specific and anti-PDL-1 antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment lowered senescence associated secretory phenotype (SASP) factors in off-target tissues in chemotherapy treated tumor-bearing mice. Thus, HCW9218 may serve as a novel therapeutic (monotherapy or in combination with chemotherapy) to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors. HCW9218 has been cleared by the U.S. Food and Drug Administration to proceed for evaluation in a first-inhuman Phase 1b clinical trial in patients with advanced pancreatic cancer. Citation Format: Pallavi Chaturvedi, Varghese George, Bai Liu, Niraj Shrestha, Meng Wang, Micheal Dee, Xiaoyun Zhu, Jack Egan, Jin-an Jiao, Catherine Spanoudis, Jilan Xing, Victor Gallo, Christian Echeverri, Lijing You, Lin Kong, Gabriela Muniz, Peter Rhode, Hing Wong. Immunotherapeutic hcw9218 enhances anti-tumor activity of chemotherapy by facilitating immune-mediated elimination of therapy induced senescent cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1299.
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Bloch, Kate M., Xingyi Shi, Fenghai Duan, George R. Washko, Avrum Spira, Denise R. Aberle, Raul S. Estepar, Ehab Billatos, and Marc E. Lenburg. "Abstract 6392: Predicting malignancy in indeterminate pulmonary nodules using quantitative CT imaging." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6392. http://dx.doi.org/10.1158/1538-7445.am2022-6392.
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Abstract With an increasing number of positive lung cancer screening trials and the growing utilization of low dose CT screening, the detection of indeterminate pulmonary nodules is an important clinical problem. A biomarker that will be able to differentiate between benign andmalignant nodules would help to accelerate diagnosis and reduce unnecessary and invasive procedures. Here, we investigated the utility of quantitative radiomics to predict malignancy of small pulmonary nodules. Data including cancer status, age, gender, smokingstatus and CT radiomics data, from 242 patients accrued from the Detection of Early Lung Cancer Among Military Personnel (DECAMP1) consortium was used. DECAMP1 is a prospective study of 500 current or former smokers with indeterminate pulmonary nodules (0.7-3.0 cm). A total of 446 quantitative radiomic features were extracted from CT images of each patient. For the prediction models, various feature selection methods and machine learning algorithms including Random Forest, Gradient Boosting Machine and Support Vector Machine were used. Data was split into train and test set with tenfold cross-validation.Models were evaluated using; Accuracy, Sensitivity, Specificity and Area under the curve - a receiver operating characteristic curve (AUC-ROC). In terms of predictive performance, the AUC value was 0.64 (95% CI: 0.50-0.78) for the clinical model and 0.77 (95% CI: 0.64-0.90) for the radiomics model. Adding clinical features to the radiomics model (gender, age, smoking status) did not improve the model. We have also investigated the slice thickness and scanner (PET vs PET-CT) variables on the models’ performance and saw a modest improvement of the AUC values when using more homogenous data. In this study, we showed the potential of radiomics for lung cancer prediction in DECAMP1.For future work, we are planning to test whether incorporating bronchial gene expression data improves lung cancer detection and to validate these findings in separate, independent cohorts. Citation Format: Kate M. Bloch, Xingyi Shi, Fenghai Duan, George R. Washko, Avrum Spira, Denise R. Aberle, Raul S. Estepar, Ehab Billatos, Marc E. Lenburg, on behalf of the DECAMP Investigators. Predicting malignancy in indeterminate pulmonary nodules using quantitative CT imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6392.
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Aduboffour, Akwasi O., Stephen J. Carter, George Howard, Saira Khan, Marquita Lewis-Thames, Justin Xavier Moore, and MPH X. Moore. "Abstract 3653: The moderating role of dietary patterns on physical health and risk of cancer mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3653. http://dx.doi.org/10.1158/1538-7445.am2022-3653.
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Abstract Diet and physical activity share an association with cancer mortality. We investigated whether empirically-defined dietary patterns modified the association between a composite of physical health and cancer mortality. METHODS: We performed analysis among participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Physical health (PH) composite was assessed by the product of baseline heart rate and systolic blood pressure, a reliable measurement of myocardial oxygen demand, and self-reported physical activity. Participant adherence was assessed with empirically-defined dietary patterns including: Convenience (including Chinese and Mexican foods, pasta, pizza), Plant-based (including fruits, vegetables), Southern (including added fats, fried foods, sugar-sweetened beverages), Sweets/Fats (including sugary foods) and Alcohol/Salads (including alcohol, green-leafy vegetables, salad dressing) was examined as an effect modifier. We performed comparisons across PH composite risk groups (i.e., severe, high, moderate, and low risk). We estimated hazard ratios (HRs) and associated 95% confidence intervals (CIs) by PH composite groups, stratified by dietary patterns. RESULTS: Among 20,857 participants, 18% were defined as severe-risk PH, 30% were high-risk, 15% were moderate-risk PH, and 38% were low-risk PH. The most common dietary pattern adhered to by severe-risk PH participants was the southern based diet (30% adhering, p value <0.01). Severe-risk PH participants generally had higher risks for cancer mortality, corresponding to a 2.4-fold increased risk of cancer mortality (adjusted HR: 2.42; 95% CI: 1.52 - 3.85) even with limited southern diet consumption (1st quartile). CONCLUSIONS: Dietary patterns influence cancer mortality risk; however cardiovascular health is independently associated with greater long-term risk of cancer death. Citation Format: Akwasi O. Aduboffour, Stephen J. Carter, George Howard, Saira Khan, Marquita Lewis-Thames, Justin Xavier Moore, PhD, MPH X. Moore. The moderating role of dietary patterns on physical health and risk of cancer mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3653.
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Zagouri, Flora, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, et al. "Abstract P1-12-01: Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–12–01—P1–12–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-12-01.
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Abstract Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS events (33.3%) had been reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus control arm A either in the entire cohort (HR=0.90, p=0.38 and HR=0.85, p=0.20) or among HER2-positive, trastuzumab-treated patients (HR=0.69, p=0.13 and HR=0.67, p=0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in DFS or OS were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033 Citation Format: Flora Zagouri, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Charisios Karanikiotis, Amanda Psyrri, Dimitrios Bafaloukos, Paris Kosmidis, Gerasimos Aravantinos, Eleni Res, Davide Mauri, Anna Koumarianou, Kalliopi Petraki, Anna Tsipoura, Dimitrios Pectasides, Helen Gogas, George Fountzilas. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial [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 P1-12-01.
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Yu, Chun I., Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T. Liu, Jacques Banchereau, and Karolina Palucka. "Abstract P5-01-05: Transcriptional signature of metastatic triple negative breast cancer in humanized mice." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–01–05—P5–01–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-01-05.
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Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among ten PDX tumors tested, four did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastases (lung and liver). We find that different TNBC PDX tumors have different metastatic potential. Their metastatic potential is linked with differences in cellular composition and transcriptional signatures at the level of the primary tumor. Interferon Response signature is enriched in primary TNBC PDXs with metastatic potential, while non-metastatic primary tumors display a TNF signature as well as allograft rejection signature. Furthermore, liver metastases were enriched in myeloid transcripts. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis. Citation Format: Chun I Yu, Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Transcriptional signature of metastatic triple negative breast cancer in humanized mice [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 P5-01-05.
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Mazumder, Aloran, Athena Jimenez, Rachel E. Ellsworth, Sophia George, Stephen J. Freedland, Matthew N. Bainbridge, and Svasti Haricharan. "Abstract P3-14-03: The DNA damage repair landscape in Black women with breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–14–03—P3–14–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-14-03.
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Abstract Black women have 42% higher mortality rate from estrogen receptor positive (ER+) breast cancer than white women. Molecular mechanisms underlying worse outcome in black women are understudied. Recently, downregulation of specific DNA damage repair (DDR) genes was shown to causally induce resistance to standard care endocrine therapy by dysregulating cell cycle regulation, and to associate with poor outcome in white women with ER+ breast cancer. However, frequency and patterns of DDR dysregulation in Black women with ER+ breast cancer and impact on survival outcomes remains untested. By assessing RNA expression of 104 DDR genes across three tumor, and two normal breast, datasets, here, we map for the first time, global patterns of DDR gene expression regulation specific to Black women, both in tumors and in the normal breast. We identify a specific subset of 8 candidate DDR genes that are dysregulated at the RNA level in tumors from Black women. Of note, a novel DDR regulation signature where genes from the homologous recombination pathway are upregulated and genes from SSBR pathways (mainly base excision repair) are coincidently downregulated is almost uniquely detectable in tumors from Black women (8% incidence relative to 1% in tumors from white women, p=0.01). Moreover, this coincident DDR signature associates with dysregulated cell cycle gene expression (p<0.001). In accordance, patients whose tumors demonstrate this coincident DDR signature also have significantly worse survival outcomes across datasets (hazard ratio of 9.5, p<0.001). Overall, these results constitute the first systematic analysis of differences in DDR gene expression regulation between Black and white women and identify a specific DDR signature associated with poor outcome in tumors from Black women. These results provide new grounds for refining biomarker profiles and improving precision medicine for underserved populations. Citation Format: Aloran Mazumder, Athena Jimenez, Rachel E Ellsworth, Sophia George, Stephen J Freedland, Matthew N Bainbridge, Svasti Haricharan. The DNA damage repair landscape in Black women with 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 P3-14-03.
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Perkins, Julian. "George Fitchett and Steve Nolan, eds, Spiritual Care in Practice: Case Studies in Healthcare Chaplaincy. London and Philadelphia, PA: Jessica Kingsley Publishers, 2015, 318 pp. (Pbk). ISBN: 978-1-84905-976-3, eISBN: 978-0-85700-87-3, £18.99." Health and Social Care Chaplaincy 5, no. 2 (February 14, 2017): 312–14. http://dx.doi.org/10.1558/hscc.31319.
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Beeghly-Fadiel, Alicia, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, and Marta A. Crispens. "Abstract 3228: Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3228. http://dx.doi.org/10.1158/1538-7445.am2022-3228.
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Abstract Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship. Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis. Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94). Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed. Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3228.
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Kumar, Roshan M., Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, et al. "Abstract 2899: Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2899. http://dx.doi.org/10.1158/1538-7445.am2022-2899.
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Abstract Regulatory T cells (Tregs) contribute to immunosuppression within the tumor microenvironment and have been associated with poor outcomes in a range of cancers. Targeted depletion of tumor-infiltrating Tregs (TITRs) is an attractive therapeutic strategy with the potential to enhance antitumor immunity in patients who do not respond to current treatments. However, such approaches have been limited to date by a lack of markers that are highly specific for TITRs. CCR8 is a chemokine G protein-coupled receptor (GPCR) that has recently been shown to be specifically expressed on TITRs as compared to Tregs in the periphery or other T cells within tumors. Here, we report the development and characterization of HFB101110, a humanized monoclonal antibody against CCR8 with potent and specific antibody-dependent cellular cytotoxicity (ADCC) activity. HFB101110 specifically recognizes an epitope on the N-terminus extracellular domain of CCR8 and does not recognize the closely related chemokine receptor CCR4. HFB101110 acts through a dual mechanism of action, by both depleting CCR8+ cells via ADCC and blocking binding of the CCL1 chemokine to its receptor CCR8. Blockade by HFB101110 inhibited calcium flux and chemotaxis induced by the interaction between CCL1 and CCR8. Furthermore, HFB101110 showed potent single agent anti-tumor activity associated with depletion of intratumoral Tregs in a human CCR8 knock-in mouse model. HFB101110 mediated specific ex vivo killing of Tregs from primary patient tumor samples both in the presence, and in some cases the absence, of allogeneic NK cells. HFB101110 showed favorable pharmacokinetic properties and a favorable developability profile, and was well-tolerated in both wild-type mice and cynomolgus monkeys. HFB101110 is currently being developed as a novel immunotherapy for the treatment of solid tumors coupled with a patient biomarker strategy derived from HiFiBiO’s Drug Intelligent Science (DIS™) single-cell immune profiling platform. Citation Format: Roshan M. Kumar, Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, Rebecca Silver, Clarisse Monchecourt, Ross B. Fulton, Qian Zhang, Nicola Beltraminelli, Bernhard Moser, Francisco Adrian, Liang Schweizer. Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2899.
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Raufi, Alexander G., Arielle De La Cruz, Andrew George, Sean Hacking, Venkateshwar Madka, Varun Prabhu, Howard Safran, et al. "Abstract 2783: Increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in normal colonic mucosa with imipridone ONC201/TIC10 treatment: A potential biomarker for chemoprevention studies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2783. http://dx.doi.org/10.1158/1538-7445.am2022-2783.
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Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States and currently the most effective method at reducing risk of death is through screening. Although these strategies have reduced the incidence of CRC, they are invasive, costly, and have low rates of compliance. Chemoprevention aims to prevent or delay the onset of CRC through eradication or prevention of precursor colonic adenomas, ideally with affordable and nontoxic drugs. The imipridone ONC201, which induces apoptosis, in part, through upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is currently undergoing preclinical evaluation as a potential chemopreventive agent. In preclinical models, we found that treatment with ONC201 is capable of increasing TRAIL expression in normal cells and can improve tumor suppression through immune surveillance by the innate immune system. To further assess potential biomarkers of response to ONC201, we evaluated expression of TRAIL and death receptor 5 (DR5), as well as markers related to cellular stemness such as LGR5 in colonic mucosa obtained from mice treated with ONC201 and vehicle controls. In this study, 16-week-old female C57BL/6 mice were administered vehicle or ONC201 50mg/kg (n=11) body weight by oral gavage twice a week for a total of five doses. Both immunohistochemistry and western blotting were used to evaluate differential expression of various potential biomarkers in both fresh frozen and FFPE colonic tissue. Using western blotting we found a significant increase in TRAIL expression in normal colonic mucosa obtained from mice treated with ONC201 as compared to vehicle controls. This finding was further validated using immunohistochemistry. Other markers, such as DR5 appeared unaffected with treatment. As efforts are currently underway to develop a CRC chemoprevention trial using ONC201, TRAIL may represent a biomarker of interest. Further analysis of stemness markers, as well as serum analyses are currently in process and may reveal other potential biomarkers for use in chemoprevention trial development. Citation Format: Alexander G. Raufi, Arielle De La Cruz, Andrew George, Sean Hacking, Venkateshwar Madka, Varun Prabhu, Howard Safran, Lanlan Zhou, Dean Brenner, Chinthalapally V. Rao, Wafik S. El-Deiry. Increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in normal colonic mucosa with imipridone ONC201/TIC10 treatment: A potential biomarker for chemoprevention studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2783.
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Kucukosmanoglu, Asli, Silvia Scoarta, Thomas Wijnands, George Kanev, Bart Westerman, Bert Kiewit, David Noske, and Tom Wurdinger. "Abstract 6312: The adverse events atlas, towards a strategy to predict synergistic adverse events of combination therapies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6312. http://dx.doi.org/10.1158/1538-7445.am2022-6312.
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Abstract The current gold-standard of estimating adverse events of a drug are clinical trials. However, these trials fail to represent real-life practice where patients have additional diseases (comorbidities) and commonly use numerous drugs when entering the clinic. Therefore, there is a rise of interest in combinational therapies, also because effective combinations are expected to prevent therapy resistance. At this moment it is not feasible to predict the adverse events of new combination therapies due to lack of available information both from a dimensionality (i.e., number of adverse events recorded per patient) as well as from a patient-number perspective. When available, this information allows to choose combinational therapies with acceptable adverse events. In this study we developed a preliminary method to predict adverse events of drug combinations in order to select combinations with a mild adverse event profile. We used the FAERS, an FDA post-marketing adverse events registry as data source containing 15 million adverse-event records. First, we developed a method to visualize the adverse events profiles of monotherapy and combination therapy using dimension reduction to accurately represent the relation between adverse events over many patients. These adverse-event profiles are then fed to a convolutional neural network (CNN) to generate an explainable prediction-model for adverse events occurring in combination therapies. The CNN trained on monotherapy is able to learn from the data and recognize adverse event patterns. The learned pattern information, as stored in the so-called latent space, can be converted back onto the original adverse event profiles. This showed a high similarity to the original data, also for unseen combination therapy effects. Furthermore, a t-SNE analysis on the latent space of the CNN is able to separate additive and synergistic adverse event patterns in combination therapy. Our CNN model can successfully learn complex adverse-event patterns for single drugs and their combinations, which are all encoded in the latent space. The developed method is therefore applicable to determine the combinatorial effects of highly complex adverse event profiles. Citation Format: Asli Kucukosmanoglu, Silvia Scoarta, Thomas Wijnands, George Kanev, Bart Westerman, Bert Kiewit, David Noske, Tom Wurdinger. The adverse events atlas, towards a strategy to predict synergistic adverse events of combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6312.
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Toshikuni, Nobuyuki, Mutsumi Tsuchishima, Mikihiro Tsutsumi, and Joseph George. "Abstract 5925: Albumin-bilirubin score as a marker for predicting occurrence of hepatocellular carcinoma in patients with liver cirrhosis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5925. http://dx.doi.org/10.1158/1538-7445.am2022-5925.
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Abstract Background: The newly developed albumin-bilirubin (ALBI) score has been proved to be a simple and useful marker for predicting prognosis in patients with hepatocellular carcinoma (HCC). However, evidence is scarce regarding the use of ALBI score to predict occurrence of HCC in patients with chronic liver disease. In the current study, we examined the usefulness of ALBI score to predict occurrence of HCC in patients with liver cirrhosis. Methods: In this retrospective study, we included only cirrhotic patients without previous history of HCC. A total of 68 cirrhotic patients (median age, 68 years old; 36 males and 32 females; 42 compensated and 26 decompensated cirrhosis) were included. Using a Cox proportional hazard model, we identified the risk factors for HCC occurrence and mortality. The potential factors were age, gender, causes of cirrhosis (hepatitis virus infection vs others), platelet count, serum alpha-fetoprotein (AFP) level, serum endocan level, ALBI score, and successful treatment for cirrhosis (yes vs no). Results: The leading cause of cirrhosis was hepatitis virus infection (9 HBV- and 20 HCV-infected patients), followed by alcohol-related liver disease (23 patients), nonalcoholic steatohepatitis (5 patients), and other causes (2 patients). The median follow-up period was 10 years. During the study period, 16 patients had HCC and 22 patients died (12 liver failure, 3 HCC, 2 variceal rupture, 2 bacterial infection, and 3 other causes). Cumulative survival rates were 92%, 72%, and 59%, at 5, 10, and 15 years, respectively. Regarding risk factors for HCC occurrence, univariate analysis identified a low platelet count and an increased ALBI score as significant factors. However, on multivariate analysis, an increased ALBI score was the only significant factor [hazard ratio, 7.49 (1.65−34.04); p = 0.009]. Regarding risk factors for mortality, univariate analysis identified older age as the only significant factor; male gender and hepatitis virus infection tended to be significant. However, on multivariate analysis, older age, male gender, and hepatitis virus infection were significant factors. Conclusion: The results indicate that an increased ALBI score is a useful factor to predict occurrence of HCC in patients with liver cirrhosis. Citation Format: Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi, Joseph George. Albumin-bilirubin score as a marker for predicting occurrence of hepatocellular carcinoma in patients with liver cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5925.
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George, Andrew, Ilyas Sahin, Shengliang Zhang, and Wafik S. El-Deiry. "Abstract 3548: Role of the cancer cell proteome and tumor microenvironment in the hyperprogression (HP) phenotype response to immune checkpoint blockade." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3548. http://dx.doi.org/10.1158/1538-7445.am2022-3548.
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Abstract Immune checkpoint blockade (ICB) immunotherapy strategies have yielded significant successes in recent years. Unfortunately, such treatments are not always successful. While tumor resistance to immunotherapy is often the reason, a subpopulation of patients treated with ICB show an acceleration in tumor growth rate, termed hyperprogressive disease (HPD) or hyperprogression (HP). Different studies have evaluated the incidence rate of HPD at 4% to 30%, though clear predictors have been elusive. An impediment to progress on investigating HPD has long been the lack of a reliable disease model. We recently reported a humanized mouse model of hyperprogression using mismatch repair deficient (MMR-d) p53-/- HCT-116 colorectal cancer cells implanted subcutaneously into athymic mice humanized with human CD8+ T-cell line TALL-104 and treated with anti-PD-1 Pembrolizumab. Flow cytometry was used to ensure the systemic establishment of the TALL-104 CD8+ human T-cells used to humanize the athymic mice and characterize immune tumor infiltration, which was not different between groups. Immunoperoxidase staining revealed increased expression of proliferation marker Ki67 within the HPD xenografts, supporting the finding that HPD tumors were exhibiting accelerated growth. Initial human cytokine analysis revealed a significant elevation in three cytokines (IFN-γ, TRAIL R2, and RANK L) and a significant decrease in four (CCL2, Chitinase 3-like 1, IL-4, and TNF-α). We attempted to mitigate HP through administration of anti-EGFR Panitumumab based on some clinical studies linking EGFR aberration to HPD but found worsened HPD in cotreated mice. We are conducting RNA sequencing to identify any changes in the RNAome of the HPD model, and immunoperoxidase analysis of resected tumor tissue for cytokine expression and cell death markers that may provide clues for accelerated growth within the HPD tumor microenvironment. Future studies will also focus on the interplay between Pembrolizumab and Panitumumab observed preliminarily to exacerbate the HPD with more comprehensive in vivo studies including of patient-derived xenotransplants. Citation Format: Andrew George, Ilyas Sahin, Shengliang Zhang, Wafik S. El-Deiry. Role of the cancer cell proteome and tumor microenvironment in the hyperprogression (HP) phenotype response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3548.
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Hu, Jiabiao, Xiangjun He, Jing Xu, Yixuan Zhou, Yanan Yue, Yangbin Gao, George Church, and Luhan Yang. "Abstract 6070: Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6070. http://dx.doi.org/10.1158/1538-7445.am2022-6070.
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Abstract Engineered human induced pluripotent stem cells (hiPSC)-derived allogeneic Natural Killer (NK) cells are emerging as promising safe and effective off-the-shelf cell therapy drugs. Repeated dosing of NK cells can partly compensate the relatively shorter persistence of NK cells compared with chimeric antigen receptor T cells (CAR-T); However, with each repeat, the persistence and efficacy are increasingly challenged by activation of host innate and adaptive immunity. Thus, reducing immunogenicity of allogeneic NK cells holds promise for better efficacy. In this study, we report a combination of “hypoimmunity” gene edits including multiple transgene knock-ins and both class I and class II MHC knockouts (2KO). We show that hiPSC engineered by the hypoimmunity combo can be efficiently differentiated into NK cells, comparable to the non-engineered ones. This is contrary to the notion from mouse studies that NK cells devoid of class I molecules are hypo-responsive, these engineered NK cells can be expanded by aAPC (artifitial Antigen Presenting Cells, a K562 cell line with surface expression of mbIL-21 and CD137L) and are capable of killing tumor cells, Additionally, we show that the engineered NK cells can evade T cell immunity, as examined by in vitro T cell proliferation and cytotoxicity assays. A humanized mouse model with transplanted CD34-positive human hematopoietic stem cells confirmed that the engineered NK cells can persist longer than WT and 2KO NK cells. Hypoimmune-QN-019 NK cells are generated by incorporating hypoimmunity gene combo edits into our hiPSC-derived NK cell clinical candidate QN-019 which has 3 transgenes including membrane-bound IL-15, high affinity non-cleavable CD16 and CAR targeting CD19. Comparing to QN-019, hypoimmune-QN-019 displayed better efficacy in humanized CDX mouse model in clearing CD19-positive cancer cells. Taken together, we have engineered hiPSC-derived allogeneic NK cells with hypoimmunity features, which hold great promise in becoming an off-the-shelf drug with improved in vivo persistence and efficacy for repeated dosing. Citation Format: Jiabiao Hu, Xiangjun He, Jing Xu, Yixuan Zhou, Yanan Yue, Yangbin Gao, George Church, Luhan Yang. Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6070.
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Zielstorff, Mark, Yiping Chen, Jeremy Presland, Alan Byford, Amy Doty, Erik Munsell, Craig Parish, et al. "Abstract 3143: RIG-I agonism promotes immune activation in syngeneic tumor model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3143. http://dx.doi.org/10.1158/1538-7445.am2022-3143.
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Abstract Activation of retinoic acid-inducible gene I (RIG-I) increases pro-inflammatory cytokine production, enhances antigen presentation, and promotes tumor cell apoptosis. Here we assessed the pharmacological activity of a RIG-I agonist encapsulated in lipid nanoparticle in the B16F10 mouse syngeneic tumor model. To probe whether additional pathways may complement RIG-I agonism, we tested our compound in combination with anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. The RIG-I agonist was administered intratumorally (IT) in B16F10 tumors. In one arm, tumors were collected four hours post treatment for cytokine analysis. In a separate arm, tumor size was measured twice a week for two weeks to assess efficacy. To understand the mechanism of action of the RIG-I agonist, high dimensional phenotyping of dissociated tumors collected at various time points was evaluated using CyTOF. Tumor-specific memory T cell response was evaluated by tumor re-challenge in vivo. Intra-tumoral dosing of the RIG-I agonist generated robust and dose-dependent production of type I IFN in the tumor that led to tumor efficacy in B16F10 model. Within 24 hours of the RIG-I agonist administration tumor infiltrating myeloid cells, NK cells, and T cells showed upregulation of activation markers such as CD69, CCR7, and Ki-67, and MHC I and PD-L1 were upregulated on CD45- cells. On day 10 of the treatment, the number of CD8+ T cells and NK cells in the tumor and their expression of granzyme B increased substantially. The RIG-I agonist dosed in combination with anti-PD-1 and anti-CTLA-4 monoclonal antibodies enhanced B16F10 tumor killing, including complete tumor regressions. No tumor growth was observed when these mice were re-inoculated with B16F10 cells. In conclusion, the RIG-I agonist encapsulated in lipid nanoparticle activates tumor infiltrating immune cells, promotes tumor killing, and combines favorably with anti-PD-1 and anti-CTLA-4 antibodies. Citation Format: Mark Zielstorff, Yiping Chen, Jeremy Presland, Alan Byford, Amy Doty, Erik Munsell, Craig Parish, Gretchen Baltus, Lily Moy, George Addona, Jie Zhang-Hoover. RIG-I agonism promotes immune activation in syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3143.