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Journal articles on the topic 'Targeted therapies, RAS, MEK, PI3K'

Author: Grafiati

Published: 9 March 2023

Last updated: 31 July 2025

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1

LaRue, Rebecca S., Hanh Nguyen, Karen Sachs, et al. "Ras-Pathway Inhibition With Targeted Therapies Abrogates Self-Renewal In Acute Myelogenous Leukemia." Blood 122, no. 21 (2013): 819. http://dx.doi.org/10.1182/blood.v122.21.819.819.

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Abstract Hyperactivated Ras-pathways serve as oncogenic drivers in multiple human tumors including acute myelogenous leukemia (AML) (Ahearn et al. Nat Rev Mol Cell Biol 2011). The specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. Recently, we have shown that NRASG12V–activated signaling pathways are critical to leukemia stem cell maintenance (Sachs et al. submitted). To elucidate which Ras-activated signaling molecules mediate self-renewal in AML, we employed a murine model that harbors Mll-AF9 and a tetracycline repressible,

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Huang, Tannie, Jon Akutagawa, Inbal Epstein, Charisa Cottonham, Maricel Quirindongo-Crespo, and Benjamin S. Braun. "Inhibition of Akt Signaling Alleviates MDS/MPN Driven By KrasD12 or Nf1 Loss." Blood 126, no. 23 (2015): 360. http://dx.doi.org/10.1182/blood.v126.23.360.360.

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Abstract Juvenile and chronic myelomonocytic leukemias (JMML and CMML) are aggressive myeloid malignancies categorized as myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). Chemotherapy has little benefit for MDS/MPN patients, and new therapies are needed. We have used mouse models investigate the potential of signal transduction inhibitors in MDS/MPN, as JMML and CMML are associated with mutations in NRAS, KRAS, PTPN11, CBL, or NF1 that activate Ras signaling. Conditional Mx1-Cre, KrasLSL-D12 (designated KrasD12) mice develop an aggressive and fully penetrant MDS/MPN characteri

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Gnoni, Antonio, Antonella Licchetta, Riccardo Memeo, et al. "Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies." Medicina 55, no. 12 (2019): 754. http://dx.doi.org/10.3390/medicina55120754.

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The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug re

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Tamura, Ryota, and Masahiro Toda. "A Critical Overview of Targeted Therapies for Vestibular Schwannoma." International Journal of Molecular Sciences 23, no. 10 (2022): 5462. http://dx.doi.org/10.3390/ijms23105462.

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Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also co

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Yoko, Yoshikawa1. "RAS Inhibition Suppresses the Progression and Metastasis of Triple-Negative Breast Cancer." Mega Journal of Case Reports 7, no. 5 (2024): 2001–15. https://doi.org/10.5281/zenodo.11236631.

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<strong>Abstract</strong> Triple<strong>-</strong>negative breast cancer (TNBC) is the most lethal subtype of breast cancer and currently lacks effective targeted therapies. Therefore, there is an urgent need to develop new therapeutic strategies for patients with TNBC; the poor prognosis of TNBC patients is linked to the overexpression of epidermal growth factor receptor (EGFR), which is involved in tumor progression, and lysyl oxidase (LOX), which is associated with metastasis. We previously reported that RAS inhibition with small-molecule pan-RAS inhibitors, such as Kobe0065, exerts antitum

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Patel, Meet, Adam Eckburg, Shahina Gantiwala, et al. "Resistance to Molecularly Targeted Therapies in Melanoma." Cancers 13, no. 5 (2021): 1115. http://dx.doi.org/10.3390/cancers13051115.

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Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been develo

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Giraud, Jean-Stephane, Doriane Gorret, Manuela Ye, et al. "Abstract 6709: NF1 mutations in lung adenocarcinoma preclinical models and potential targeted therapies: The crucial role of the RAS-MAPK pathway." Cancer Research 85, no. 8_Supplement_1 (2025): 6709. https://doi.org/10.1158/1538-7445.am2025-6709.

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Targeting tumor suppressor genes, such as NF1, is a major challenge in cancer. Somatic NF1 mutations are found in ∼15% of lung adenocarcinoma (LUAD) cases. Still, the molecular vulnerabilities and cellular adaptations associated with these mutations remain unclear. Therefore, we aimed to study the functional consequences of NF1 loss in LUAD and its impact on the RAS/MAPK pathway, as well as potential therapeutic strategies. We established isogenic NF1-mutated cellular models (mono- and bi-allelic NF1 mutations) using CRISPR-Cas9 technology on the HBE4-E6/E7-C1 human bronchial epithelial cell l

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Derwich, Aleksandra, Monika Sykutera, Barbara Bromińska, Błażej Rubiś, Marek Ruchała, and Nadia Sawicka-Gutaj. "The Role of Activation of PI3K/AKT/mTOR and RAF/MEK/ERK Pathways in Aggressive Pituitary Adenomas—New Potential Therapeutic Approach—A Systematic Review." International Journal of Molecular Sciences 24, no. 13 (2023): 10952. http://dx.doi.org/10.3390/ijms241310952.

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Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and potential for metastasis are unknown. RAF/MEK/ERK and mTOR signaling are significant pathways in the regulation of cell growth, proliferation, and survival, its importance in tumorigenesis has been highlighted. The aim of our review is to determine the role of th

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Przestrzelska, Magda, Iga Ślesicka, Natalia Zozula, et al. "Advances in Targeted Therapies and Combination Approaches for Melanoma: A Comprehensive Review." Quality in Sport 23 (October 3, 2024): 54869. http://dx.doi.org/10.12775/qs.2024.23.54869.

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Introduction and Purpose: Melanoma, an aggressive malignancy from melanocytes, has a poor prognosis. Despite advances in targeted therapies and immunotherapies, drug resistance remains a challenge. This review examines the molecular pathways involved in melanoma and therapeutic strategies targeting them, aiming to improve patient outcomes and overcome treatment resistance by understanding genetic alterations and signaling cascades driving melanoma progression. State of Knowledge: Melanoma arises from genetic predisposition and UV radiation exposure, involving mutations in pathways like RAS/RAF

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Afonso, Mariana, and Maria Alexandra Brito. "Therapeutic Options in Neuro-Oncology." International Journal of Molecular Sciences 23, no. 10 (2022): 5351. http://dx.doi.org/10.3390/ijms23105351.

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One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase rec

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Czarnecka, Anna M., Ewa Bartnik, Michał Fiedorowicz, and Piotr Rutkowski. "Targeted Therapy in Melanoma and Mechanisms of Resistance." International Journal of Molecular Sciences 21, no. 13 (2020): 4576. http://dx.doi.org/10.3390/ijms21134576.

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The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted thera

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Rager, Taylor, Adam Eckburg, Meet Patel, et al. "Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies." Cancers 14, no. 15 (2022): 3779. http://dx.doi.org/10.3390/cancers14153779.

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Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, me

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Dexheimer, Thomas S., Thomas Silvers, Nathan P. Coussens, Rabih Said, Beverly A. Teicher, and James H. Doroshow. "Abstract C045: Combinations of PI3K inhibitors with targeted oncology agents in multicellular spheroid models." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): C045. http://dx.doi.org/10.1158/1535-7163.targ-23-c045.

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Abstract Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway plays a significant role in cancer, and inhibitors offer a promising strategy for targeted therapies. The selectivity of current inhibitors varies against different PI3K isoforms or subtypes. For example, alpelisib and inavolisib predominantly target the α-isoform, whereas duvelisib targets the δ- and γ-isoforms. By contrast, copanlisib is a pan-PI3K inhibitor, exhibiting activity against all isoforms. In combinations with other targeted agents, we investigated the activity of these four PI3K inhibitors against multicel

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Breese, Erin Haag, Brian Turpin, Phillip Dexheimer, et al. "Molecular signatures and responses to targeted therapies in over 300 relapsed and therapy-refractory young adult (AYA) and childhood cancers." Journal of Clinical Oncology 35, no. 15_suppl (2017): 11514. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11514.

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11514 Background: Contemporary chemotherapy-based regimens provide cures for most pediatric & AYA cancers. However, for patients with relapsed/refractory malignancies, outcomes are poor & imply a distinct and aggressive biology. Identifying common themes in the molecular architecture & oncogenic mechanisms in these patients is a critical priority for drug development. We hypothesized that the molecular signature of cancers in these patients would be independent of histology. We also assessed the response to molecular alteration (MA)-targeted therapies. Methods: IRB-approved analysi

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Vachhani, Pankit, Prithviraj Bose, Mohamed Rahmani, and Steven Grant. "Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML." Physiological Genomics 46, no. 13 (2014): 448–56. http://dx.doi.org/10.1152/physiolgenomics.00173.2013.

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Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activa

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Tamura, Ryota. "Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis." International Journal of Molecular Sciences 22, no. 11 (2021): 5850. http://dx.doi.org/10.3390/ijms22115850.

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Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor pr

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Sadeghian, Dorsay, Wan-Hsin Lin, James Smadbeck, et al. "Abstract 3391: Dual inhibition of RAS and the IGF2/IGF1R pathways: a potential targeting strategy for RAS-mutated embryonal rhabdomyosarcoma." Cancer Research 83, no. 7_Supplement (2023): 3391. http://dx.doi.org/10.1158/1538-7445.am2023-3391.

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Abstract Background: Mutations in RAS is reported in embryonal rhabdomyosarcoma (ERMS). Upregulation of IGF2/IGF1R axis and IGF2 overexpression is a common finding. Targeting RAS downstream is associated with high toxicity. Combination therapies targeting parallel pathways is necessary to overcome treatment resistance. Dual inhibition of RAS downstream and IGF2/IGF1R axis can be a potential mechanism of targeted treatment. The efficacy of this mechanism was studied using a microcancer 3D exvivo tumor cell viability assay in a KRAS mutant ERMS. Design: Tumor was collected for a high-risk pediat

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Lu, Yen-Jung, Kien Thiam Tan, Chun-Jung Chen, et al. "Targeted gene sequencing panel for identifying actionable genomic alterations in Taiwanese lung cancer patients." Journal of Clinical Oncology 35, no. 15_suppl (2017): e20522-e20522. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20522.

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e20522 Background: Lung cancer boasts an arsenal of targeted therapies directed at various molecular aberrations such as EGFR mutations and fusion genes. Simultaneous assessment for genetic alterations provides biomarkers to assist clinicians in their treatment selections. Methods: A total of 43 FFPE (formalin-fixed, paraffin-embedded) samples obtained from lung cancer patients in Taiwan were subjected to next-generation sequencing (NGS), using a compact panel encompassing 17 potentially actionable, lung cancer-associated genes. NGS was performed on the Ion Torrent PGM or Proton System with a

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Potu, Harish, Sara A. Little, Stephanie Fedorchak, et al. "Abstract 608: NEOS-223 is a small molecule kinase inhibitor which induces apoptosis in selected cancer models." Cancer Research 84, no. 6_Supplement (2024): 608. http://dx.doi.org/10.1158/1538-7445.am2024-608.

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Abstract Due to their critical role in cancer signaling pathways, members of the kinase family have emerged as one of the most comprehensively pursued targets in pharmacological cancer research. Deregulation of kinase activities leads to a variety of upstream and downstream signaling pathway changes in cancer cell. The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR cascades are activated by genetic alterations in selected upstream signaling molecules such as receptor tyrosine kinases. Recently developed therapies which target such kinases (EGFR, BRAF, MEK) with kinase inhibitors have notably improved the p

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Gibson, M. K., H. Mezzadra, L. Kleinberg, et al. "Predicting and monitoring tumor response to epidermal growth factor receptor inhibitor gefitinib in patients with locally advanced esophageal adenocarcinoma." Journal of Clinical Oncology 25, no. 18_suppl (2007): 14112. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14112.

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14112 Background: This study aimed to validate an ex vivo chemosensitivity assay to measure the pharmacodynamic effect of gefitinib on esophageal adenocarcinoma (EAC) prior to treatment with pre-operative concomitant chemoradiotherapy (CRT). Methods: A 14 day run-in period with 250 mg/day of gefitinib preceded CRT. Endoscopic biopsies (D 0 and 14) in 4 patients with T2–3N0/1M0/1a EAC were analyzed by ex vivo chemosensitivity assay. Day 0 tissue was exposed to gefitinib ex vivo, then tumor was exposed to gefitinib for 14 days in vivo (ie in the patient). Phosphorylation of the EGFR, raf/MEK/ERK

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Tsimberidou, Apostolia Maria, David S. Hong, Jennifer J. Wheler, et al. "Precision medicine: Clinical outcomes including long-term survival according to the pathway targeted and treatment period–The IMPACT study." Journal of Clinical Oncology 36, no. 18_suppl (2018): LBA2553. http://dx.doi.org/10.1200/jco.2018.36.18_suppl.lba2553.

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LBA2553 Background: We evaluated the impact of pathway targeted and long-term follow-up of patients (pts) with refractory cancers referred to phase I trials. Methods: Pts referred to our program (2007-2013) had CLIA molecular testing. Pts treated with matched targeted therapy (MTT) vs. non-matched therapy (NMT) were analyzed. Results: Of 3,743 pts who had testing, 1,307 had ≥1 alteration and received therapy (MTT 711, NMT 596): med. age 57 yrs, range 16-86; 39% men; med. no. of prior therapies 4, range 0-16. The most common tumors were gastrointestinal 24.2%, gynecologic 19.4%, breast 13.5%, m

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Williams, Gareth, Alexander Llewelyn, Robert Thatcher, Keeda-Marie Hardisty, and Marco Loddo. "Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma." PLOS ONE 17, no. 3 (2022): e0245817. http://dx.doi.org/10.1371/journal.pone.0245817.

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The standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked. To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data gener

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Loskutov, Jürgen, Gerrit Erdmann, Anja Arndt, et al. "Abstract 187: Let’s get physiological! Impact of media conditions on drug response to targeted therapies in CRC organoids." Cancer Research 83, no. 7_Supplement (2023): 187. http://dx.doi.org/10.1158/1538-7445.am2023-187.

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Abstract Physiologically relevant in vitro tumor models are crucial in any research setting from drug development to individualized treatment predictions. Patient-derived 3D cell culture models (PD3D®) are validated cancer models which recapitulate the biology of the donor tissue from genotype to phenotype. A multitude of PD3D® replicates can be generated and these are suitable for high-throughput-screening. However, the influence of media conditions on specific drug sensitivity profiles widely remains elusive and thus the predictive value of screenings is obscured. Here we have investigated p

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Nobre, Liana, Adrian Levine, Scott Milos, et al. "BIOM-09. GUIDING PRECISION THERAPEUTICS THROUGH INTERROGATING ONCOGENIC PATHWAY ACTIVATION." Neuro-Oncology 24, Supplement_7 (2022): vii5—vii6. http://dx.doi.org/10.1093/neuonc/noac209.019.

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Abstract The deregulation of canonical oncogenic pathways are largely responsible for driving pediatric cancers and can be targeted for therapeutics. Currently, we interrogate these pathways clinically by looking for gene mutations, but these are not found in all cases, and in others multiple genes are. We hypothesized that assessing transcriptomic and proteomic-based pathway activation will allow a better understanding of the most active oncogenic pathways and help guide therapy. To do this, we developed and validated a nanostring based assay that interrogates 4 key actionable pathways (MAPK,

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Obrador, Elena, Paz Moreno-Murciano, María Oriol-Caballo, et al. "Glioblastoma Therapy: Past, Present and Future." International Journal of Molecular Sciences 25, no. 5 (2024): 2529. http://dx.doi.org/10.3390/ijms25052529.

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Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms i

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Teo, M., H. T. Huynh, S. W. Hee, et al. "FOXO3a predicts for survival and its phosphorylated form is downregulated following mTOR or MEK inhibitor therapy in Hepatocellular Carcinoma." Journal of Clinical Oncology 25, no. 18_suppl (2007): 4538. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4538.

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4538 Background: Hepatocellular carcinoma (HCC) is an aggressive cancer endemic in Asia with few effective treatments. We hypothesize that FOXO3a may be a potential prognostic marker in HCC and analyze the effects of targeted therapy acting on the PI3K/AKT pathway, of which FOXO3a is downstream. PI3K activates serine/threonine protein kinase AKT, causing FOXO3a phosphorylation and its nuclear translocation, promoting apoptosis. Tumor suppressor, promyelocytic leukemia (PML), inactivates nuclear phosphorylated AKT (pAKT). mTOR, also of the P13K/AKT pathway, is dysregulated in many cancers. PI3K

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Yaktapour, Niuscha, Christine Dierks, Dietmar Pfeifer, et al. "Combination Of Kinase Inhibitors Overcomes B-Raf Inhibitor-Induced Paradoxical ERK Activation In CLL Cells In Vitro – Potential Implications For CLL Treatment." Blood 122, no. 21 (2013): 4121. http://dx.doi.org/10.1182/blood.v122.21.4121.4121.

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Abstract Chronic lymphocytic leukemia (CLL) remains incurable with current state of the art therapy creating the need for novel therapeutic concepts. Kinase inhibitors represent a promising strategy in the treatment of various malignancies including CLL. However, based on the recent experience with other targeted therapy compounds used as single agents, it appears important to identify additional targets and to evaluate therapeutic combinations targeting two or more critical signaling hubs in CLL cells. This strategy is likely to counteract the development of drug resistance more efficiently.

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Seale, Tessa, Brandy Perkins, Theodora Chatzilygeroudi, et al. "Pan-RAS Inhibitor RMC-7977 Overcomes Oncogenic RAS Signaling and Exerts Antileukemic Effects in CMML/AML Cells." Blood 144, Supplement 1 (2024): 5784. https://doi.org/10.1182/blood-2024-211218.

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by overlapping features of both myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN). Patients with CMML have dismal outcomes with a median survival of 20-30 months, and this is partly due to their poor responses to the standard-of-care treatment with hypomethylating agents. Thus, new treatments are urgently needed for CMML patients. RAS mutations are detected in roughly 50% of CMML patients and in even higher frequency among patients who progress to acute myeloid leukemia (AML).

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Chowdhury, Saikat, Ichiaki Ito, Vinay K. Pattalachinti, et al. "Abstract 4317: Targeting KRAS in appendiceal cancer: promising results with MRTX1133 and RMC-6236 in organoids and PDX models." Cancer Research 85, no. 8_Supplement_1 (2025): 4317. https://doi.org/10.1158/1538-7445.am2025-4317.

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Abstract Oncogenic KRAS mutations are frequent in mucinous appendiceal adenocarcinoma (AA) (63.4%), with G12D accounting for just over half (50.9%) and G12V representing 23.0%. There remains a significant unmet need for effective targeted therapies of AA. The advent of novel RAS inhibitors, such as KRASG12D inhibitor MRTX1133 and Pan-RAS inhibitor RMC-6236, offer a promising opportunity to address this therapeutic gap by directly targeting this oncogene. Here, we investigate the therapeutic impacts of these two new inhibitors in preclinical models of AA tumors. One AA organoid model with KRASG

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Lilleberg, Stan L., Jeffrey Durocher, Jill Hempel, et al. "In-Depth Mutation Scanning of Signaling Pathway Genes Involved in the Development and Targeted Treatment of Hematopoietic Malignancies." Blood 106, no. 11 (2005): 4399. http://dx.doi.org/10.1182/blood.v106.11.4399.4399.

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Abstract The Raf/MEK/ERK, Wnt/beta-catenin, JAK/STAT and PI3K/Akt signal transduction pathways have key roles in the regulation of cell cycle progression and apoptosis, and are current focal points of therapeutic development and intervention strategies for hematopoietic neoplasias. These pathways have several regulatory components that keep proliferative and anti-apoptotic mechanisms in check, but which can also drive neoplastic processes when their functions are altered by genetic and epigenetic events. Links between critical pathways are also being established and, although only partially un

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Stanley, Karly A., Jared D. Almazan, Tursun Turapov, et al. "Abstract 4127: Combined inhibition of RAF, MEK, and FAK attenuates melanoma brain metastases and prolongs survival in preclinical models." Cancer Research 84, no. 6_Supplement (2024): 4127. http://dx.doi.org/10.1158/1538-7445.am2024-4127.

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Abstract Despite promising results from recent FDA-approved therapies, many advanced melanoma patients develop resistance to both immunotherapy and targeted therapy. A common resistance mechanism to targeted therapy is upregulation of the PI3K/AKT signaling pathway, which has also been shown to promote the development of melanoma brain metastases. Historically, AKT inhibitors have failed in the clinic due to their limited efficacy or intolerable toxicity. Proteomic analysis comparing non-metastatic vs brain metastatic primary tumors in mice revealed focal adhesion kinase (FAK) as an AKT1 speci

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Flandrin-Gresta, Pascale, Lydia Campos, Emmanuelle Tavernier-Tardy, Amelie Duval, Nathalie Nadal, and Denis Guyotat. "Activation of Multiple Signal Transduction Pathways as a Prognostic Marker in Acute Myelogenous Leukemia." Blood 110, no. 11 (2007): 2395. http://dx.doi.org/10.1182/blood.v110.11.2395.2395.

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Abstract Deregulation of signal transduction pathways (STPs) including JAK/STAT, RAS/Raf/MEK/ERK and PI3K/AKT may promote leukemogenesis by conferring cells proliferation and survival advantages in acute myelogenous leukemia (AML). The activation of these pathways had an adverse prognosis in AML and development of targeted therapies seems to be promising. Heat-shock proteins (HSP) are involved in the conformational maturation of a number of signaling proteins, and HSPs expression in AML is associated with other adverse prognostic factors (Bcl2, MRP). The aim of this work was to study STPs expr

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Altunel, Erdem, Jason Somarelli, So Young Kim, Wayne Glover, Gabrielle Rupprecht, and Shiaowen David Hsu. "A precision medicine strategy to identify the FGFR pathway as a novel target in colorectal cancer liver metastasis." Journal of Clinical Oncology 36, no. 4_suppl (2018): 660. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.660.

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660 Background: Colorectal cancer liver metastasis (CRCLM) continues to be a major health problem and despite extensive efforts to develop new drugs, median survival remains at a mere 30 months. The purpose of our study is 1. Develop a precision medicine strategy for patients with CRCLM and 2. Discover novel pathways and treatments to improve outcomes. Methods: In order to develop a precision medicine strategy, 6 matched patient derived xenografts (PDX) and cell lines were established from patients undergoing resection of their CRCLM. A high-throughput drug screen containing over 100 FDA appro

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McQueen, Teresa, Marina Konopleva, and Michael Andreeff. "Activity of Targeted Molecular Therapeutics Against Primary AML Cells: Putative Role of the Bone Marrow Microenvironment." Blood 106, no. 11 (2005): 2304. http://dx.doi.org/10.1182/blood.v106.11.2304.2304.

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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow (BM) microenvironment such as mesenchymal stem cells (MSC). It is speculated that specific BM niches may provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. In this study, we compared anti-leukemia effects of Ara-C and various signal transduction and apoptosis inhibitors in a co-culture system of primary AML and human bone marrow-derived MSC. AML blasts from 11 primary AML samp

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Salinas, Ryan, Daniel Zhang, Fadi Jacob, et al. "TMOD-25. GLIOBLASTOMA ORGANOIDS: A MODEL SYSTEM FOR PATIENT-SPECIFIC THERAPEUTIC TESTING." Neuro-Oncology 21, Supplement_6 (2019): vi268. http://dx.doi.org/10.1093/neuonc/noz175.1124.

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Abstract Glioblastoma treatment options remain limited due to its aggressive and invasive nature. It is increasingly appreciated that molecular heterogeneity between tumors and within tumors likely contributes to the lack of therapeutic advances. To maintain the inherent heterogeneity of glioblastoma, we employed a novel method to rapidly culture glioblastoma organoids (GBOs) directly from neurosurgical resection. GBOs are routinely generated around two weeks following initial resection. Comprehensive histologic and sequencing analyses demonstrated similarity to primary tumors. Leveraging clin

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36

Petronczki, Özlem Yüce, Laura Pisarsky, Petra Lujza Szabó, et al. "Abstract 4564: Therapeutic potential of SOS1 and KRAS inhibitors in malignant peripheral nerve sheath tumors." Cancer Research 84, no. 6_Supplement (2024): 4564. http://dx.doi.org/10.1158/1538-7445.am2024-4564.

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Abstract Neurofibromatosis type 1 (NF1) is a genetic disorder that affects the nervous system. It is caused by mutations in the NF1 gene. NF1 loss of function leads to elevated RAS signaling, which plays a crucial role in cell growth and proliferation. Due to the dysregulated RAS signaling, individuals with NF1 are prone to the development of neurofibromas. These neurofibromas are typically benign and called Plexiform Neurofibromas (PNFs), in some cases, they can transform into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly aggressive and invasive cancers that contribute

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Schade, Andrew E., Anna M. Jankowska, Hadrian Szpurka, and Jaroslaw P. Maciejewski. "Pharmacologic Inhibition of Src Family Kinases Differentially Affects T Cell Cytokine Production and Proliferation: Implications for Novel Immunomodulatory Therapies." Blood 110, no. 11 (2007): 1349. http://dx.doi.org/10.1182/blood.v110.11.1349.1349.

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Abstract It is well-recognized that the T cell receptor (TCR) signaling pathway, catalyzed by the Src family kinase (SFK) Lck, is the essential first step in T cell immune responses. The long-held goal of specifically targeting SFK activity for immunomodulatory therapy is becoming more of a reality as SFK inhibitors are entering into clinical use. In particular, dasatinib is an oral small molecule inhibitor of Abl and SFK, including Lck. Given the central importance of Lck in transmitting signals from the TCR signaling complex, and the potent ability of dasatinib to inhibit Lck activity, we hy

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Meintani, Angeliki, Eirini Papadopoulou, Georgios Tsaousis, et al. "Increasing targeted therapy options for mCRPC patients using multigene NGS panel." Journal of Clinical Oncology 41, no. 16_suppl (2023): e17056-e17056. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17056.

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e17056 Background: Prostate cancer (PCa) represents the second most common malignancy in males, characterized by a high level of clinical and molecular heterogeneity. Eventually, many patients develop metastatic Castration Resistant Prostate Cancer (mCRPC). mCRPC refers to prostate cancer that has spread beyond the prostate gland and is associated with increased morbidity and mortality. Next Generation Sequencing (NGS) has led to the identification of genomic alterations that may represent actionable targets with therapeutic potential in mCRPC. Such alterations can be identified on the somatic

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Sacilotto, Natalia, Cristina Mascaró, Edgar Creus, et al. "Abstract A061: The LSD1 inhibitor iadademstat shows preclinical efficacy in malignant peripheral nerve sheath tumor cells and synergistic effects in combination." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): A061. http://dx.doi.org/10.1158/1535-7163.targ-23-a061.

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Abstract Background: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and rare malignancies accounting for 10% of all tissue sarcomas. Around 50% develop in patients with neurofibromatosis type 1 carrying mutations in the NF1 gene and the other 50% occur sporadically. NF1 is a tumor suppressor gene and a negative regulator of RAS signaling pathway. However, mutation of the NF1 gene is not sufficient to drive MPNST and a series of further mutational events must accumulate in genes other than NF1, such as in CDKN2A and PRC2 complex components. Mutations in p53 or PTEN and/

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Bartlett, John M., Cheryl Crozier, Vinay K. Mittal, et al. "Abstract 5548: Clinical management and decision making in early ER-positive breast cancers through improved prognosis and pathway directed molecular profiling." Cancer Research 83, no. 7_Supplement (2023): 5548. http://dx.doi.org/10.1158/1538-7445.am2023-5548.

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Abstract Hormone receptor positive (HR+ve) breast cancer (BCa) comprises over 80% of all newly diagnosed BCas. While there is an initial good response to anti-hormone therapies, many patients will experience a recurrence. Validated prognostic tests are used to guide chemotherapy decisions, but the goal of precision medicine has yet to be achieved. We developed and validated a 95-gene prognostic signature (Bayani et al 2017) from the TEAM trial (van de Velde et al, 2011), demonstrating this risk classifier performed as well as the 21-gene, 50-gene and 70-gene tests and can be used in HER2+/-ve

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Tsimberidou, Apostolia Maria, Siqing Fu, David S. Hong, et al. "Results of IMPACT 2, a randomized study evaluating molecular profiling and targeted agents in metastatic cancer at MD Anderson Cancer Center." Journal of Clinical Oncology 42, no. 16_suppl (2024): 3153. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.3153.

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3153 Background: To address the limitations of exploratory studies, we conducted IMPACT2. The primary endpoint was to compare the progression-free survival (PFS) between patients treated with matched targeted therapies (MTT) selected on the basis of tumor molecular alterations and those whose treatment was not selected on the basis of alteration analysis (non-targeted therapy, NTT). Methods: Patients with metastatic cancer and targetable alterations were randomized between the 2 arms when eligibility criteria were met (Part A, 5/2014-4/2017; sponsor, Foundation Medicine). In Part B (3/2019-9/2

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Majumder, Muntasir M., David Tamborero, Pekka Anttila, et al. "DNA Damage Repair Pathway Alterations in Multiple Myeloma Predict Poor Prognosis, but Correlate with Sensitivity to IGF1R-PI3K-mTOR and HDAC Inhibitors." Blood 128, no. 22 (2016): 198. http://dx.doi.org/10.1182/blood.v128.22.198.198.

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Abstract Introduction Although several novel drugs have recently been approved or are in development for multiple myeloma (MM), there are few molecular indicators to guide treatment selection. In addition, the impact of recurrent myeloma alterations on drug response is often unclear. To address these limitations and elucidate genotype to phenotype relationships in myeloma, we comprehensively analyzed 100 MM samples and compared genomic, transcriptomic, and cytogenetic information to ex vivo drug response profiles and clinical outcome of individual MM patients. Our results reveal novel insights

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Allegretti, Matteo, Maria Rosaria Ricciardi, Martina Vincenzi, et al. "The Phosphatidylinositol-3-Kinase Inhibitor BKM120 Impairs Proliferation and Induces Pro-Apoptotic Effects In Acute Myeloid Leukemia." Blood 122, no. 21 (2013): 4222. http://dx.doi.org/10.1182/blood.v122.21.4222.4222.

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Abstract Acute myeloid leukemia (AML) has been characterized by a growing number of recurrent genetic alterations, frequently causing the constitutive activation of signal transduction pathways, which result in enhanced blast proliferation and prolonged survival. Despite the increased understanding of AML biology, prognosis of these patients remains, generally, severe. Therefore, novel therapies targeted on aberrant signaling are now under evaluation. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a pivotal role in the control of cell growth, pr

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Lu, Hao, Xi Zhang, Shengwen Liu, et al. "Comprehensive genomic analysis of salivary gland carcinomas in a Chinese population." Journal of Clinical Oncology 41, no. 16_suppl (2023): e18094-e18094. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e18094.

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e18094 Background: Salivary gland carcinomas (SGCs) represent a heterogeneous group of poorly characterized head and neck tumors, which are rare and challenging to treat. A strategy based on molecular screening and targeted therapy seems to be the best approach for treating patients with SGCs in the future, whereas the genomic mechanisms of SGCs are largely unclear. Methods: A total of 49 patients with histologically confirmed SGCs, including mucoepidermoid carcinoma (MEC, n = 10), adenoid cystic carcinoma (ACC, n = 20), carcinoma ex pleomorphic adenoma (cxPA, n = 10) and other pathological ty

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Pemovska, Tea, Mika Kontro, Bhagwan Yadav, et al. "Identification Of AML Subtype-Selective Drugs By Functional Ex Vivo Drug Sensitivity and Resistance Testing and Genomic Profiling." Blood 122, no. 21 (2013): 482. http://dx.doi.org/10.1182/blood.v122.21.482.482.

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Introduction Adult acute myeloid leukemia (AML) exemplifies the challenges of modern cancer drug discovery and development in that molecularly targeted therapies are yet to be translated into clinical use. No effective second-line therapy exists once standard chemotherapy fails. While many genetic events have been linked with the onset and progression of AML, the fundamental disease mechanisms remain poorly understood. There is significant genomic and molecular heterogeneity among patients. Several targeted therapies have been investigated for improved second-line AML therapy but none has been

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Kornblau, Steven M., Chenyu W. Hu, Suk Young Yoo, et al. "Classification Of Acute Myelogenous Leukemia (AML) Based On Functionally Related Proteins Groups." Blood 122, no. 21 (2013): 492. http://dx.doi.org/10.1182/blood.v122.21.492.492.

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Abstract Background In an era where the recognized heterogeneity of the pathophysiology of AML is increasing rapidly due to sequencing and other “omics” platforms, and where the number of available targeted therapeutics is also rapidly expanding, a means to individually match therapies to AML on a specific basis is needed. New targeted therapies modulate single pathways, so recognizing when a particular pathway is active is crucial, but mutations are rare within most of these pathways in AML. Furthermore pathway activation can arise by various means. Finally the interaction of multiple differe

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Liu, Dazhi, Yonina R. Murciano-Goroff, Justin Jee, et al. "Clinicopathologic characterization of ERK2 E322K mutation in solid tumors: Implications for treatment and drug development." Journal of Clinical Oncology 40, no. 16_suppl (2022): 3135. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3135.

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3135 Background: MAPK1 encodes ERK2, a kinase component of the mitogen activated signaling (MAPK) pathway. ERK2 E322K is a known activating mutation that leads to increased phosphorylation and ERK signaling. In vitro studies found this mutation to be associated with resistance to dabrafenib, trametinib, but potential sensitivity to ERK inhibitors. Despite its potential as a drug target, little is known about the clinicopathologic characteristics of this hotspot mutation across solid tumors. Methods: Patients with solid tumors underwent tumor next-generation sequencing at Memorial Sloan Ketteri

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Mehnert, Martin, Xiaoxi Xu, Tobias Treiber, et al. "Abstract 185: Global mapping of pathway modules and phosphorylation networks in PDX and corresponding organoid (PDXO) models treated with targeted therapies." Cancer Research 83, no. 7_Supplement (2023): 185. http://dx.doi.org/10.1158/1538-7445.am2023-185.

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Abstract Introduction: Multi-omics-based strategies in precision medicine, including genomic, transcriptomic and proteomic data, have contributed to the molecular-level characterization of cancers and the identification of novel driver genes, as well as a better comprehension of resistance mechanisms. Patient-derived tumor models, including patient-derived xenograft (PDX) and in vitro 3D organoid counterparts (PDXO), are widely recognized as predictive preclinical cancer models closely recapitulating both tumor complexity and patient response and enabling the study of tumor identity for person

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Cho, William C., Ka-Po Tse, Kien-Thiam Tan, et al. "Abstract 5787: Identification of genomic alterations in lymphoepithelioma-like carcinoma by next-generation sequencing." Cancer Research 82, no. 12_Supplement (2022): 5787. http://dx.doi.org/10.1158/1538-7445.am2022-5787.

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Abstract Introduction: Lymphoepithelioma-like carcinoma (LELC) is a special pathological tumor exclusive to Asians and EBV infection. As LELC is rare, the genetic picture is not very clear. Our study aims to identify the genomic alterations (GAs) and novel potential predictive biomarkers for LELC by next-generation sequencing (NGS). Materials and Methods: A retrospective search was performed to retrieve the LELC samples from Queen Elizabeth Hospital (Hong Kong SAR, China). We identified 38 pathologically confirmed LELC patients with archived surgically resected samples. Of these, 22 tissue spe

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Sorokin, Alex, Lea Bitner, Ji Wu, David Menter, Scott Kopetz, and Van Karlyle Morris. "Antitumor activity of panRAF inhibition in BRAF V600E metastatic colorectal cancer." Journal of Clinical Oncology 35, no. 4_suppl (2017): 616. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.616.

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616 Background: BRAF V600E mutations, present in <10% of patients with metastatic colorectal cancer (mCRC), are associated with low responses to chemotherapy and poor survival outcomes. Targeted therapies against BRAF and EGFR have shown promising clinical activity. The panRAF inhibitor (PRI) LSN3074753 inhibits dimerization of all RAF isoforms to impede downstream MEK activation, with no reflexive MAPK reactivation common with other BRAF inhibitors. Anti-tumor activity of PRI has not been compared to BRAF + EGFR inhibition in patient-derived xenograft (PDX) models of BRAF V600E mCRC. Metho

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