tbuckley/cabot-search huggingface dataset:
Abstract 6564: SOS1 inhibitor treatment improves response to Venetoclax in acute myeloid leukemia
Authors: Kaja Kostyrko, Melanie Hinkel, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Daniel Gerlach, Irene Waizenegger
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. First-line treatment of AML patients consists primarily of chemotherapy, sometimes combined with a targeted therapy. However, elderly patients unfit for chemotherapy receive venetoclax, a BCL2 inhibitor, combined with azacitadine or decitabine. While responses in these patients are high (50-70%, with median OS of 10-17 months), around 30-50% of them do not respond and most relapse within 1-10 years. Increased MAPK pathway activity or low frequency RAS pathway mutations have been identified as key mediators of resistance to standard-of-care targeted therapies for AML, including venetoclax. Here, we found that in DepMap whole-genome CRISPR screens, leukemia cell lines, including AML, show a particular dependency on SOS1. A subsequent PRISM screen with a selective inhibitor of SOS1 confirmed these results. To validate these results in vitro, we treated 7 AML cell lines showing strongest dependency on SOS1 based on DepMap and PRISM screens, with SOS1i or a SHP2 inhibitor. We found that in 4 of 7 cell lines treatment with SOS1i or SHP2i strongly impaired proliferation. In 3 of 4 responding cell lines, the anti-proliferative effect with either SOS1i or SHP2i was stronger than azacytidine single agent treatment. We next treated 29 primary ex vivo cultures of AML with SOS1i and found that the treatment induced strong or intermediate anti-proliferative effect in 21 of 29 models (72%). In two AML PDX models, treatment with SOS1i as a single agent resulted in approximately 25% reduction of human CD45+ AML blast cells in both models. Venetoclax treatment led to approximately 75% decrease in AML blasts, while the combined venetoclax and SOS1i treatment resulted in near complete eradication of the disease. Annexin V staining of AML monoblasts demonstrated that this decrease was due to an increase in apoptosis in the combination groups. In summary, we demonstrate that SOS1 inhibitor treatment may be used to improve responses to venetoclax in AML patients. Citation Format: Kaja Kostyrko, Melanie Hinkel, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Daniel Gerlach, Irene Waizenegger. SOS1 inhibitor treatment improves response to Venetoclax in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6564.
Abstract 923: Biomarker use in oncology approvals in the US
Authors: Yannan Nancy Dou, Christian Grimstein, Jian Wang, Jacques Mascaro
Journal: Cancer Research (2024)

Abstract Introduction: Precision medicine through the use of biomarkers has revolutionized the way we understand and combat cancer. We are summarizing the current state and challenges of biomarker use in the context of cancer therapeutic products approved by the United States Food and Drug Administration (FDA). Methods: We curated a dataset of oncology therapeutic products approved by the FDA through the regular and accelerated pathways from 2011 to 2022, based on publicly available FDA database, approval letters and reviews, prescribing information, publications, and clinicaltrial.gov. Results: During the period of 2011 to 2022, the FDA granted 132 accelerated and 331 regular approvals for 80 and 144 oncology therapeutic products with 133 and 340 new indications, respectively. The percentage of approvals for a biomarker-defined population was higher in accelerated approvals in comparison to regular approvals (i.e., 51% vs. 39%). The five disease sites with the highest number of approved indications were leukemia, lung, non-Hodgkin lymphoma, breast, and skin. The vast majority of lung and breast cancer indications were approved in a biomarker-defined population through a range of different biomarkers. Overall, HER2-, EGFR-, BRAF-, HR-, and ALK-defined populations received the highest numbers of approvals. The most common biomarkers linked to the approval of a specific cancer type include Philadelphia chromosome for leukemia, EGFR/ALK for lung cancer, HER2/HR for breast cancer, BRAF for skin cancer, and BRCA for ovarian cancer. Multiple myeloma, kidney cancer, and Hodgkin lymphoma did not have any approval with a biomarker-defined population. Non-Hodgkin lymphoma had a large number of approvals, but the percentage approved for a biomarker-defined population was small. dMMR, MSI-H or dMMR, BRAF mutation, NTRK fusions, TMB H, and RET fusions are biomarkers linked to tissue-agnostic indications approved for solid tumors only through the accelerated pathway. Conclusion: To the best our knowledge, the analysis represents the most comprehensive overview of the current landscape on integration of biomarker in oncology therapeutic products approved by the FDA through both the accelerated and regular pathways. Our analysis shows that the FDA has increasingly approved indications based on biomarkers, particularly through the accelerated approval pathway. Biomarkers are reshaping cancer therapy under an evolving regulatory landscape with a growing emphasis on precision medicine that promises continued progress in personalized cancer care. Citation Format: Yannan Nancy Dou, Christian Grimstein, Jian Wang, Jacques Mascaro. Biomarker use in oncology approvals in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 923.
Abstract 4899: Interface-guided phenotyping of coding variants in the transcription factor RUNX1
Authors: Kivilcim Ozturk, Rebecca Panwala, Jeanna Sheen, Kyle Ford, Nathan Jayne, Dong-Er Zhang, Stephan Hutter, Torsten Haferlach, Trey Ideker, Prashant Mali, Hannah Carter
Journal: Cancer Research (2024)

Abstract Understanding the consequences of single amino acid substitutions in cancer driver genes remains an unmet need. Perturb-seq provides a tool to investigate the effects of individual mutations on cellular programs. Here we deploy SEUSS, a Perturb-seq like approach, to generate and assay mutations at physical interfaces of the RUNX1 Runt domain. We measured the impact of 115 mutations on RNA profiles in single myelogenous leukemia cells and used the profiles to categorize mutations into three functionally distinct groups: wild-type (WT)-like, loss-of-function (LOF)-like and hypomorphic. Notably, the largest concentration of functional mutations (non-WT-like) clustered at the DNA binding site and contained many of the more frequently observed mutations in human cancers. Hypomorphic variants shared characteristics with loss of function variants but had gene expression profiles indicative of response to neural growth factor and cytokine recruitment of neutrophils. Additionally, DNA accessibility changes upon perturbations were enriched for RUNX1 binding motifs, particularly near differentially expressed genes. Overall, our work demonstrates the potential of targeting protein interaction interfaces to better define the landscape of prospective phenotypes reachable by amino acid substitutions. Citation Format: Kivilcim Ozturk, Rebecca Panwala, Jeanna Sheen, Kyle Ford, Nathan Jayne, Dong-Er Zhang, Stephan Hutter, Torsten Haferlach, Trey Ideker, Prashant Mali, Hannah Carter. Interface-guided phenotyping of coding variants in the transcription factor RUNX1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4899.
Abstract 2182: 15-lipoxygenase-1 modulation of colonic resolvin production to suppress colorectal carcinogenesis
Authors: Xiangsheng Zuo, Yoshiyuki Kiyasu, Yi Liu, Micheline Moussalli, Bo Wei, Peiying Yang, Imad Shureiqi
Journal: Cancer Research (2024)

Abstract Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are widely used dietary supplements and FDA-approved treatments. The reported impacts of fish oil, DHA, and EPA on colorectal carcinogenesis (CRC) have spurred debates, as certain studies suggest promotional effects while numerous others emphasize suppressive effects. Nevertheless, resolvins, oxidative metabolites of EPA and DHA, exhibit the ability to inhibit crucial pathways (such as TNF-α and IL-1β) that contribute to CRC. 15-lipoxygenase-1 (ALOX15) plays a crucial role in the oxidative metabolism of DHA and EPA, ultimately leading to the formation of resolvins. However, ALOX15 expression is commonly lost during human CRC. Whether loss of ALOX15 expression modulates the effects of DHA and EPA on CRC remains to be elucidated. We therefore conducted the experiments in preclinical CRC mouse models induced by Azoxymethane or Apc gene mutation to explore the hypothesis that ALOX15 expression in colonic epithelial cells regulates DHA and EPA metabolism to generate resolvins, subsequently influencing CRC outcomes. We found that 1) DHA and EPA exert differential effects on CRC, which can be further modified by factors such as their formulation (e.g., ethyl ester versus triglyceride); 2) targeted transgenic expression of ALOX15 in the intestines of mice (referred to as ALOX15-Gut mice) markedly augmented the production of resolvins and concurrently suppressed CRC; 3) the predominant products from the expressed ALOX15 enzymatic activity were identified as 17-HDHA and resolvin D5; and 4) the effects ALOX15 on increasing resolvin generation and suppressing CRC were consistent across various promoters used to drive ALOX15 transgenic expression in mice. These findings collectively underscore the profound importance of ALOX15 intestinal expression as a host-related factor in resolvin generation from EPA and DHA, which subsequently contributes to the suppression of CRC. Citation Format: Xiangsheng Zuo, Yoshiyuki Kiyasu, Yi Liu, Micheline Moussalli, Bo Wei, Peiying Yang, Imad Shureiqi. 15-lipoxygenase-1 modulation of colonic resolvin production to suppress colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2182.
Abstract 7300: Synergistic inhibition of prostate cancer growth by the combination of xanthohumol and ursolic acid
Authors: Rachel Clark, Achinto Saha, Chelsea A. Friedman, Ruggiero Gorgoglione, Stefano Tiziani, John DiGiovanni
Journal: Cancer Research (2024)

Abstract Within the United States, prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer, and approximately 1 in 8 men will receive a diagnosis in their lifetime. As the second leading cause of cancer deaths in American men, about 1 in 41 will die because of prostate cancer. The World Health Organization has suggested that approximately one-third of all cancer deaths are preventable, and one of the suggested means of prevention is through the increased consumption of fruits and vegetables. Fruits and vegetables contain natural compounds known as phytochemicals which possess biological activity including some anti-cancer effects. By adapting the ATP-bioluminescence assay for cell viability, our laboratory screened a natural compound library to find combinations of these compounds that may synergistically inhibit PCa cell viability. One of the combinations to emerge from this screening process was xanthohumol (XAN) and ursolic acid (UA). We examined the ability of the combination to inhibit tumor growth in a mouse HMVP2 PCa allograft tumor model. Mice were fed diets supplemented with either XAN (0.2%) or UA (0.2%) alone or the combination. Mice on the combination diet showed a significant inhibition of HMVP2 PCa tumor growth compared to mice on the single-agent diets. In addition, in vitro studies were performed to support the allograft tumor study and to further examine the mechanism of action of the combination. A cell survival assay utilizing six different PCa cell lines indicated that the combination of XAN and UA synergistically inhibited the survival of all cell lines as calculated by the Bliss index. Mechanistic studies performed in PCa cells indicate that the combination of XAN and UA inhibits oncogenic signaling better than either agent alone. Additionally, unbiased metabolomics revealed that the tumors from mice fed the combination diet had significantly less S-adenosyl-L-methionine compared to all other groups. Overall, 13 metabolic pathways were significantly different in the tumors from mice fed the combination diet compared to all other groups. The current data suggest that using a combination of XAN and UA may be a valuable chemopreventive strategy for PCa in humans. Funding: This work was supported by NIH Grant CA228404. Citation Format: Rachel Clark, Achinto Saha, Chelsea A. Friedman, Ruggiero Gorgoglione, Stefano Tiziani, John DiGiovanni. Synergistic inhibition of prostate cancer growth by the combination of xanthohumol and ursolic acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7300.
Abstract 6587: Discovery of molecular glue of FBXW7:MYC interaction using small molecule microarray
Authors: Shenghao Guo, Morgan Stilgenbauer, Bocheng Wu, Yatin Mankan, Angela N. Koehler
Journal: Cancer Research (2024)

Abstract MYC deregulation is a key driver and feature of many human cancers. Yet, despite its importance in cancer progression, MYC is considered “undruggable” by small molecules due to its disordered conformation. Therefore, interfering with its interactions with protein partners to modulate MYC activity appears viable. FBXW7 is an E3 ligase, which serves as a constituent of the SCF (Skp1-Cul1-F box) ubiquitin ligase complex. It mediates the degradation of both c-Myc and Cyclin E through ubiquitin-dependent proteolysis. FBXW7 mutations are found in various human tumor types, establishing its role as a general human tumor suppressor. Specifically, FBXW7 down-regulation increases MYC level, and its expression correlates to lethal outcomes of breast epithelial cells, poor prognosis in glioblastoma, and T cell acute lymphoblastic leukemia remission. Therefore, our project aims to discover potent small molecule glues that would enhance the interaction between FBXW7 and MYC, leading to MYC degradation through proteolysis and eventually suppression of various cancers. Taking advantage of our high throughput screening technology, Small Molecule Microarrays (SMMs), we successfully identified 29 compounds that potently bind to both c-Myc and FBXW7 after screening our 65,000 ‘drug-like’ small molecule library. We then performed secondary assays using a mCherry-GFP MYC reporter cell line to identify our lead compound, KI-FBX-001, which decreases MYC’s expression:transcription ratio by over 50% compared to control. Additionally, this down-regulation can be rescued by protease inhibitor MG132, indicating that the effect is achieved via proteolysis. In vitro dose-response and time-course treatment revealed an optimal drugging concentration at 15uM in K562 cells, with inhibition reaching its peak at the 4-hour time point at over 60%. Using the Qiagen MYC reporter assay, the in vitro IC50 of KI-FBX-001 is found at 7.42uM. Beyond the protein level, the qPCR result also reveals a decrease in MYC mRNA level at over 70%. Surface Plasmon Resonance (SPR) is used to confirm direct binding between FBXW7 and KI-FBX-001, which showed promising binding with kd=0.17µM. Proximity Ligation Assay further confirms KI-FBX-001’s effect in enhancing FBXW7:MYC interaction in the cell. In summary, our findings proved that KI-FBX-001 is a promising molecular glue in the FBXW7:MYC interaction, and can effectively modulate the MYC level for future therapeutic purposes. Citation Format: Shenghao Guo, Morgan Stilgenbauer, Bocheng Wu, Yatin Mankan, Angela N. Koehler. Discovery of molecular glue of FBXW7:MYC interaction using small molecule microarray [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6587.
Abstract 7134: Treatment of pancreatic cancer cells with tumor treating fields (TTFields) and PARP inhibitors
Authors: Hila Ene, Kerem Ben Meir, Antonia Martinez-Conde, Roni Frechtel-Gerzi, Hila Gabay, Daria Gerasimova, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Yoram Palti
Journal: Cancer Research (2024)

Abstract Background: Therapeutic options for advanced stage pancreatic cancer are limited. Patients harboring germline BRCA mutations benefit from PARP inhibitors (PARPi); unfortunately, such mutations are rare in pancreatic cancer. Tumor Treating Fields (TTFields), electric fields that disrupt cellular processes crucial for cancer cell viability, have shown effectiveness against pancreatic cancer cells, and are currently under clinical investigation for the treatment of patients with pancreatic cancer. The mechanism of action of TTFields in various cancer types has suggested involvement of BRCA downregulation. The current study examined the potential sensitization of BRCA wild-type pancreatic cancer cell lines to PARPi with TTFields application. Methods: BxPC3 and AsPC1 human pancreatic BRCA wild-type cancer cells were treated for 72 h with TTFields (frequency of 150 kHz; intensity of 1 and 0.5 V/cm RMS, respectively), using the inovitro device. The PARPi niraparib and olaparib were each administered to the cells at various concentrations, with or without co-application of TTFields. At treatment cessation, cell count, colony formation, and apoptosis were measured. Results: Applying PARPi to pancreatic cell lines yielded a dose-dependent cytotoxic and anti-clonogenic effects, and induced apoptosis. TTFields application also induced such effects when applied alone, while delivery of TTFields together with PARPi amplified the effects demonstrated by PARPi alone. Conclusions: Concomitant application of TTFields and PARPi in BRCA wild type pancreatic cancer cells exhibits a potential improvement relative to the mono-therapies. This could be rationalized based on the previously demonstrated ability of TTFields to induce a state of BRCAness in cancer cells, and suggests benefit for TTFields and PARPi co-treatment in the absence of background BRCA mutations. Citation Format: Hila Ene, Kerem Ben Meir, Antonia Martinez-Conde, Roni Frechtel-Gerzi, Hila Gabay, Daria Gerasimova, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Yoram Palti. Treatment of pancreatic cancer cells with tumor treating fields (TTFields) and PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7134.
Abstract 3042: Unraveling the mechanism of YAP toxicity in neuroendocrine solid tumors: Insights from Merkel cell carcinoma
Authors: Furkan Bahar, Thomas C. Frost, Varsha Ananthapadmanabhan, Julia L. Schnabel, Manisha Thakuria, James A. DeCaprio
Journal: Cancer Research (2024)

Abstract The Hippo pathway, a pivotal regulator orchestrating organ size and tissue growth, has emerged as a central player in cancer biology. The downstream transcription factor YAP within this pathway has been implicated in diverse oncogenic processes. YAP activation contributes to drug resistance, metastasis, and poor clinical outcomes in many solid tumors. Conversely, YAP exhibits growth-suppressive effects in neuroendocrine (NE) solid cancers, a paradox that remains poorly understood. Analysis of RNAseq data from the Cancer Cell Line Encyclopedia (CCLE) revealed a distinct classification of tumors into YAP1-expressing (YAPon) and non-expressing (YAPoff) subgroups, with hematopoietic malignancies and NE solid tumors featured prominently in the latter. Merkel cell carcinoma (MCC) is a rare, high-grade, NE carcinoma of the skin with two distinct etiologies. Virus-positive MCC contains integrated Merkel cell polyomavirus that expresses the viral T antigens and virus-negative MCC caused by sunlight exposure and extensive UV damage. Bulk RNAseq performed with more than 60 MCC tumors revealed that YAP expression displayed an inverse correlation with an NE gene expression signature. To gain insight into why YAP expression is so low in MCC, we generated MCC cell lines with inducible expression of YAP. Expression of YAP led to growth arrest and cell death. We performed a genome-wide CRISPR-Cas9 screen to identify genes that when lost enable MCC cells to tolerate YAP expression. Functional enrichment analysis of the positively selected genes uncovered a variety of signaling pathways. Intriguingly, the CRISPR screen revealed a positive enrichment of non-canonical BAF complex members, including BRD9 and SMARCD1. To validate this finding, we treated MKL-1 cells with a BRD9 inhibitor, observing a substantial reduction in YAP toxicity. These findings open avenues for the development of targeted therapeutic strategies for high grade NE cancers, addressing a critical gap in our understanding of YAP biology in the context of MCC and beyond. Citation Format: Furkan Bahar, Thomas C. Frost, Varsha Ananthapadmanabhan, Julia L. Schnabel, Manisha Thakuria, James A. DeCaprio. Unraveling the mechanism of YAP toxicity in neuroendocrine solid tumors: Insights from Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3042.
Abstract 3968: Class I HLA-independent lysis of cancer cells by tumor-infiltrating CD8 T cells
Authors: Hongyan Xie, Aiping Jiang, Jonathan Perera, Aonkon Dey, Neal Smith, Moshe Sade-Feldman, Robert T. Manguso, Nir Hacohen, Russell W. Jenkins
Journal: Cancer Research (2024)

Abstract T cell-based therapies have transformed cancer treatment, although intrinsic or acquired resistance develops in nearly half of the patients. Tumor-infiltrating CD8+ T lymphocytes (TILs) are key determinants of anti-tumor immunity by secretion of cytotoxic granules, such as granzymes and perforin, and effector cytokines, such as TNFa and IFNg. A deep understanding of how CD8+ TILs eliminate cancer cells will help identify resistance mechanisms and develop new therapeutic strategies. Here, we demonstrate that TILs eliminated matched melanoma cells in a time and dose-dependent manner but in a class I HLA-independent fashion. Specifically, blocking class I HLA-TCR interaction either by the deletion of B2M (resulting in loss of class I HLA surface expression) or TCR genes did not alter the activity of these TILs. We further confirmed that TIL-mediated killing is contact-dependent. After excluding the potential roles of CD1d and MR1-restrictive T cells, gamma delta T cells, and NKG2D in TIL-mediated killing, a whole-genome CRISPR/Cas9 screen was performed in cancer cells. We identified that genes involved in JAK-STAT and cell-extrinsic apoptosis pathways are necessary for TIL-mediated killing. Together, these findings demonstrate that expanded CD8 TILs from melanoma patients are capable of eliminating melanoma cells via a novel, class I MHC-independent mechanism by coactivation of both JAK-STAT and cell-extrinsic apoptosis pathways. Citation Format: Hongyan Xie, Aiping Jiang, Jonathan Perera, Aonkon Dey, Neal Smith, Moshe Sade-Feldman, Robert T. Manguso, Nir Hacohen, Russell W. Jenkins. Class I HLA-independent lysis of cancer cells by tumor-infiltrating CD8 T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3968.