tbuckley/cabot-search huggingface dataset:
Abstract 4228: PRISM cancer cell viability profiling enables insights into clinical candidate target selectivity: A case study revealing the most selective PRMT5 inhibitors for cancers with MTAP loss
Authors: Laura Doherty, Colleen Harrington, Mustafa Kocak, Anthony Fazio, John Davis, Emily Reeves, Rachael Barry, Claudine Mapa, Dennie Frederick, Alvin Kalathungal, Jillian Eskra, Tenzin Sangpo, Melissa Ronan, William Sellers, Matthew Rees, Jennifer Roth
Journal: Cancer Research (2025)

Abstract PRISM is a highly multiplexed, genomic barcode-based cell line viability technology of nearly 1000 solid tumor and hematopoietic cell lines, which enables profiling of cellular responses to small molecules or biologics to discover biomarkers of sensitivity and resistance and generate mechanistic hypotheses. In addition to the genomic characterization of PRISM cell lines, we have generated large pharmacologic perturbation reference datasets such as the ever-growing PRISM Oncology Reference dataset, in which hundreds of clinical stage agents are systematically profiled for cell viability effects. To highlight the capability of PRISM to uncover novel insights regarding agent selectivity, here we describe the results of profiling seven unique protein arginine methyltransferase 5 (PRMT5) targeting agents (six inhibitors and one degrader). PRMT5 is a methyl transferase capable of methylating arginines on histones and non-histone protein substrates involved in important cellular processes such as growth and migration. Homozygous deletions of the PRMT5 regulator, methylthioadenosine phosphorylase (MTAP) occur in 10% of all cancers, including 40% of glioblastomas, 25% of pancreatic adenocarcinomas, and 15% of NSCLCs. Loss of MTAP leads to accumulation of methylthioadenosine (MTA) and partial inhibition of PRMT5, creating a potential therapeutic window for further inhibition of PRMT5. Our results reveal that the MTA-cooperative PRMT5 targeting agents are more selective for this target patient population (cancers with MTAP loss) compared to earlier classes of PRMT5 inhibitors. Additionally, our results suggest the PRMT5 degrader we tested does have on-target activity, but its effectiveness may be dampened by MDR1-mediated efflux. Taken together, these results showcase the capabilities of the PRISM assay to characterize clinical candidates for selectivity within the patient population of interest and uncover potential liabilities (such as drug transporter efflux). Citation Format: Laura Doherty, Colleen Harrington, Mustafa Kocak, Anthony Fazio, John Davis, Emily Reeves, Rachael Barry, Claudine Mapa, Dennie Frederick, Alvin Kalathungal, Jillian Eskra, Tenzin Sangpo, Melissa Ronan, William Sellers, Matthew Rees, Jennifer Roth. PRISM cancer cell viability profiling enables insights into clinical candidate target selectivity: A case study revealing the most selective PRMT5 inhibitors for cancers with MTAP loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4228.
Abstract 4612: Development of an Integrated Microfluidic Chip for CAR T-Cell Therapy: A Preclinical Trial-on-Chip Tool
Authors: Xuejia Kang, Lang Zhou, Weiqiang Chen, Zongliang Yue, Pengyu Chen
Journal: Cancer Research (2025)

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising outcomes in treating leukemia, yet it confronts significant hurdles due to severe side effects like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Furthermore, existing preclinical evaluation platforms often fall short in accurately replicating the human tumor microenvironment, leading to extended development durations and elevated costs. To overcome these challenges, we have developed an innovative, integrated microfluidic chip equipped with microarchitectural features that precisely mimic tumor niches, thus enhancing the modeling of CAR T-cell therapy. This chip incorporates an integrated biosensor for real-time cytokine detection, providing essential insights into cytokine dynamics throughout the therapy process. This advanced chip enables spatiotemporal monitoring of CAR T-cell functionality by observing key processes such as T-cell extravasation, target recognition, and leukemia cell destruction. Additionally, it supports the detailed examination of immune cell interactions, including those with monocytes and basophils, which are critical for understanding the side effects of CAR T therapy, particularly its impact on neuronal tolerance. By meticulously tracking these dynamics, our tool not only refines the precision of therapy modeling but also deepens our understanding of the immune response and potential toxicities associated with CAR T-cell therapy. Our investigations using the chip have yielded detailed profiles of cytokine levels across various therapy phases, including remission, resistance, and relapse. Moreover, the chip is capable of evaluating the effects of compounds in inhibiting cytokine release. This cutting-edge tool significantly shortens the development timeline, reduces costs, and enhances the physiological relevance of preclinical evaluations for CAR T-cell therapy. The implementation of this ‘(pre-)clinical-trial-on-chip’ platform is poised to revolutionize CAR T-cell therapy by facilitating the development of personalized therapies and informing clinical decision-making processes. Our findings represent a transformative step forward in the optimization and safety profiling of CAR T-cell therapies. Citation Format: Xuejia Kang, Lang Zhou, Weiqiang Chen, Zongliang Yue, Pengyu Chen. Development of an Integrated Microfluidic Chip for CAR T-Cell Therapy: A Preclinical Trial-on-Chip Tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4612.
Abstract 3889: Access and selection shapes peritoneal metastasis evolution in colorectal cancer
Authors: Emma CE Wassenaar, Alexander N. Gorelick, Wei-Ting Hung, David M. Cheek, Emre Kucukkose, I-Hsiu Lee, Martin Blohmer, Sebastian Degner, Peter Giunta, Rene MJ Wiezer, Mihaela G. Raicu, Inge Ubink, Sjoerd J. Klaasen, Nico Lansu, Emma V. Watson, Ryan B. Corcoran, Genevieve Boland, Gad Getz, Geert JPL Kops, Dejan Juric, Jochen K. Lennerz, Djamila Boerma, Onno Kranenburg, Kamila Naxerova
Journal: Cancer Research (2025)

Whether metastasis in humans can be accomplished by most primary tumor cells or requires the evolution of a specialized trait remains an open question. To evaluate whether metastases are founded by non-random subsets of primary tumor lineages requires extensive, difficult-to-implement sampling. We have realized an unusually dense multi-region sampling scheme in a cohort of 26 colorectal cancer patients with peritoneal metastases, reconstructing the evolutionary history of on average 28.8 tissue samples per patient with a microsatellite-based fingerprinting assay. To assess metastatic randomness, we evaluate inter- and intra-metastatic heterogeneity relative to the primary tumor and find that peritoneal metastases are more heterogeneous than liver metastases but less diverse than locoregional metastases. Metachronous peritoneal metastases exposed to systemic chemotherapy show significantly higher inter-lesion diversity than synchronous, untreated metastases. Projection of peritoneal metastasis origins onto a spatial map of the primary tumor reveals that they often originate at the deep-invading edge, in contrast to liver and lymph node metastases which exhibit no such preference. Furthermore, peritoneal metastases typically do not share a common subclonal origin with distant metastases in more remote organs. Synthesizing these insights into an evolutionary portrait of peritoneal metastases, we conclude that the peritoneal-metastatic process imposes milder selective pressures onto disseminating cancer cells than the liver-metastatic process. Peritoneal metastases’ unique evolutionary features have potential implications for staging and treatment. Citation Format: Emma CE Wassenaar, Alexander N. Gorelick, Wei-Ting Hung, David M. Cheek, Emre Kucukkose, I-Hsiu Lee, Martin Blohmer, Sebastian Degner, Peter Giunta, Rene MJ Wiezer, Mihaela G. Raicu, Inge Ubink, Sjoerd J. Klaasen, Nico Lansu, Emma V. Watson, Ryan B. Corcoran, Genevieve Boland, Gad Getz, Geert JPL Kops, Dejan Juric, Jochen K. Lennerz, Djamila Boerma, Onno Kranenburg, Kamila Naxerova. Access and selection shapes peritoneal metastasis evolution in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3889.
Abstract 3839: MIG-6 plays as a tumor suppressor to inhibit angiogenesis by downregulating HDAC1 in PTEN-deficient endometrial cancer
Authors: Shamsun Nahar, Jiyoung Yu, Haeam Lee, Rong Li, Jin-Seok Jung, Tae Hoon Kim, Kyunggon Kim, Jung-Yoon Yoo, Jae-Wook Jeong
Journal: Cancer Research (2025)

Abstract Endometrioid endometrial cancer (EEC) is the most prevalent gynecological malignancy. Metastatic and recurrent endometrial cancer is incurable with currently available standard therapies. While Mig-6 mutation develops distant metastasis and recurrence of EEC with Pten deficiency, Mig-6 overexpression (Ptend/dMig-6over mice) suppresses tumor development. Therefore, there is an urgent need to explore the mechanisms of tumor metastasis and recurrence to further elucidate the progression of EEC. We performed RNA-seq analysis to identify targets of Mig-6 in Ptend/d and Ptend/dMig-6over mice. The transcriptomic analysis identified 104 and 518 genes significantly increased or decreased transcripts in Ptend/dMig-6over mice compared to Ptend/d mice. The pathway analysis of these dysregulated genes showed significant inhibition of immune, inflammatory, and angiogenesis pathways in Ptend/dMig-6over compared to the Ptend/d mice group, where the key regulator was hypoxia-inducible factor-1 (HIF1A). Immunohistochemical analysis of HIF1A and PECAM1 validated a significant reduction of angiogenesis in Ptend/dMig-6over mice. Moreover, combined interactome and immunoprecipitation analyses revealed that MIG-6 directly binds with histone deacetylase 1 (HDAC1) in the EEC of Ptend/dMig-6over mice. Our double immunofluorescence results confirmed colocalization of two proteins in EEC. Finally, we evaluated the therapeutic effect of Panobinostat, a HDAC inhibitor, in EEC of Ptend/d mice. Our results demonstrate the tumor suppressor role of MIG-6 as an HDAC1 interacting protein in angiogenesis of EEC. Our findings highlight potential molecular targets of EEC that could significantly enhance therapeutic strategies for endometrial cancer. Citation Format: Shamsun Nahar, Jiyoung Yu, Haeam Lee, Rong Li, Jin-Seok Jung, Tae Hoon Kim, Kyunggon Kim, Jung-Yoon Yoo, Jae-Wook Jeong. MIG-6 plays as a tumor suppressor to inhibit angiogenesis by downregulating HDAC1 in PTEN-deficient endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3839.
Abstract 3458: Antagonism between tumors and lymphocytes drives coevolutionary processes throughout metastasis
Authors: Cort B. Breuer, Marcos Labrado, Nathan E. Reticker-Flynn
Journal: Cancer Research (2025)

Abstract The development of metastatic disease is a conserved feature across most solid organ malignancies and accounts for the majority of cancer-related deaths. While adaptations within the local immune microenvironment of primary tumors are well-appreciated hallmarks of tumor progression, there remains much unknown about the specific impact of metastasis on both local and systemic immune responses. Here, we present an analysis of changes in the adaptive immune response to tumors during metastasis and clonal selection. Our group previously developed a syngeneic melanoma mouse model of spontaneous lymph node metastasis, performing nine generations of in vivo serial passaging to select for metastatic phenotypes. As previous work suggests, we find that tumors undergo clonal selection during metastasis using lentivirus integration mapping to measure clonality. Even amidst reduced genomic diversity, we find that metastases exhibit comparable or increased transcriptomic diversity when compared to primary tumors. In light of this discordance between genomic and transcriptomic diversity, we ask whether the immune response, especially T cells, exhibit similar dynamics. Performing both bulk and single cell T cell receptor (TCR) sequencing, we find that T cell clonality mirrors the reduced clonal diversity of metastatic tumors both in the total T cell compartment and specifically in regulatory T cells. Through paired investigation of evolution of tumors and the responding immune cells, we develop a model of tumor-immune coevolution in which reduced tumor clonality selects for narrower T cell repertoires; yet, diverse tumor transcriptional profiles support the differentiation of a variety of T cell subsets that are advantageous for tumors including regulatory T cells and exhausted CD8+ T cells. We further perturb this dynamic by evolving new metastatic cell lines in the absence of T cell pressure, finding unique evolution of metastatic pathways when the immune system is altered, impairing metastasis when reimplanted into immunocompetent mice. This model of tumor-immune coevolution establishes the importance of ongoing, dynamic communication between the host and tumors throughout metastatic progression. Citation Format: Cort B. Breuer, Marcos Labrado, Nathan E. Reticker-Flynn. Antagonism between tumors and lymphocytes drives coevolutionary processes throughout metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3458.
Abstract 7432: Transformer-based glioma patient recurrence prediction model infers novel genetic markers
Authors: Ko-Hong Lin, Kai Zhang, Dung-Fang Lee, Xiaoqian Jiang
Journal: Cancer Research (2025)

Abstract Approximately 90% of glioma patients experience recurrence after initial treatment, leading to poor prognosis and short survival time. While established genetic markers, such as IDH mutation and 1p/19q codeletion, are linked to glioma prognosis, there is a critical need to identify novel targets associated with recurrence to overcome therapeutic challenges. In this study, we developed a transformer-based deep learning model to predict glioma recurrence by integrating multi-omics data, including mutations and copy number variations, from the Glioma Longitudinal Analysis (GLASS) Consortium. Our model outperformed traditional machine learning approaches, including support vector machines, logistic regression, and decision trees, achieving the best performance when utilizing mutational features alone, while copy number variations were less informative. Feature importance analysis identified key contributors to glioma recurrence, including frequently mutated genes such as TP53, ATRX, and PTEN, as well as novel markers like MUC16, TTN, and CIC. Our approach represents an early application of state-of-the-art deep learning to dissect the genomic drivers of glioma recurrence, offering valuable insights for developing targeted therapies to improve patient outcomes. Citation Format: Ko-Hong Lin, Kai Zhang, Dung-Fang Lee, Xiaoqian Jiang. Transformer-based glioma patient recurrence prediction model infers novel genetic markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7432.
Abstract 1677: Navitoclax, a Bcl-2/xL inhibitor, and YM155, a survivin inhibitor, in combination with carboplatin effectively inhibit ovarian cancer tumor growth
Authors: Tejas Samantaray, Hilary Kenny, Lucy Kelliher, Ernst R. Lengyel, Carman K.M. Ip, Kasjusz Kordylewicz, Rachael Hoffmann, Sarah Rauch, Beatrice Malacrida, Sophie Skingsley, Frances R. Balkwill, Chiara Battistini, Ugo Cavallaro, Wolf R. Wiedemeyer
Journal: Cancer Research (2025)

Abstract Introduction: High-grade serous ovarian cancer (OvCa) is generally treated with upfront chemotherapy, including carboplatin. Recurrent disease is driven by the persistence of platinum-resistance cells. Experimental Procedures: A high throughput screen (HTS), using a 3D organotypic culture assembled with extracellular matrix, primary human fibroblasts, and mesothelial cells, was established and validated. Using a library of FDA approved drugs, the 3D HTS was performed with the goal of identifying a combination of drugs that synergistically target two populations of OvCa, aldehyde dehydrogenase (ALDH) high and ALDH low enzyme activity cells, that are less sensitive to carboplatin treatment than the bulk OvCa cells. Summary of Results. Initial results showed that Omipalisib, Verteporfin, CA3, Mitoxantrone, Navitoclax, Venetoclax and YM155 had significant single drug activity in either the ALDH low or both the ALDH low/high cell populations. Synergistic drug activity was identified with three drug combinations, Navitoclax/Omipalisib, Navitoclax/YM155, and YM155/Omipalisib. In vitro the combination of Navitoclax/YM155 was most efficient at blocking primary human OvCa sphere formation and the proliferation of four different OvCa cell lines in the 3D organotypic culture. In vivo the combination of Navitoclax/YM155/carboplatin decreased the total number and weight of metastases, decreased the percentage of ALDH high OvCa cells in tumors, and increased survival when compared to carboplatin treatment alone in xenograft models. Conclusion: Our results suggest that the combination of Navitoclax/YM155/carboplatin has promise as a therapy for the treatment of OvCa. Citation Format: Tejas Samantaray, Hilary Kenny, Lucy Kelliher, Ernst R. Lengyel, Carman K.M. Ip, Kasjusz Kordylewicz, Rachael Hoffmann, Sarah Rauch, Beatrice Malacrida, Sophie Skingsley, Frances R. Balkwill, Chiara Battistini, Ugo Cavallaro, Wolf R. Wiedemeyer. Navitoclax, a Bcl-2/xL inhibitor, and YM155, a survivin inhibitor, in combination with carboplatin effectively inhibit ovarian cancer tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1677.
Abstract 4192: Preclinical characterization of LAE122, a novel, potent and selective WRN inhibitor for the treatment of MSI-H tumors
Authors: Ming Li, Minhua Zhang, Junyan Chen, Chaojun Cai, Xiaofen Lin, Justin Gu
Journal: Cancer Research (2025)

Abstract DNA mismatch repair (dMMR) deficiency could induce damage of genome, resulting Microsatellite instability (MSI-H), which is frequently observed in various tumor types, including colorectal, gastric, endometrial, and ovarian cancers. Although immune checkpoint inhibitors (ICI) have been approved for the treatment of MSI-H tumors, significant unmet medical need remains across several tumor types that fail to respond or relapse with ICI therapies. Werner syndrome ATP-dependent helicase (WRN) is a RecQ family helicase that plays important roles in DNA repair and in the maintenance of genome integrity. Recent studies have identified WRN as a promising synthetic lethal drug target for MSI-H cancers. LAE122 is a novel, potent and selective WRN inhibitor developed by Laekna through structure-based drug design strategy. LAE122 has highly differentiated structure from bench-mark molecules and displayed single digit nanomolar IC50 values in biochemical assay and cell anti-proliferation assay on MSI-H cells but had no effect on Microsatellite stability (MSS) cells up to 10 µM. LAE122 demonstrated favorable drug-like properties, including good in vitro ADMET and in vivo PK with low plasma clearance and high oral bioavailability across animal species. In SW48 and HCT116 CDX models, LAE122 showed robust anti-tumor growth effect at lower doses than bench-mark molecules with strong evidence on biomarker change. LAE122 didn’t have off-target liability in in vitro assays and demonstrated good tolerability in preclinical toxicology studies. In conclusion, LAE122 is a novel, potent and selective WRN inhibitor for the treatment of MSI-H tumors. Citation Format: Ming Li, Minhua Zhang, Junyan Chen, Chaojun Cai, Xiaofen Lin, Justin Gu. Preclinical characterization of LAE122, a novel, potent and selective WRN inhibitor for the treatment of MSI-H tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4192.
Abstract 5169: Validation of genetically defined Oncopig hepatocellular carcinoma cell lines for <i>in vitro</i> evaluation of targeted therapeutic efficacy
Authors: Mahmoud Khalafalla, Navin Viswakarma, Lobna Elkhadragy, Theresa K. Kelly, Mark Eccleston, Lawrence B. Schook, Ron C. Gaba, Kyle M. Schachtschneider
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death worldwide with a 5-year survival rate of 18%. Development of novel targeted therapeutics to advance HCC precision medicine approaches is challenging due to a lack of malleable large animal HCC models that replicate human genetics, anatomy, metabolism, and physiology. We previously demonstrated our ability to develop HCC cell lines and tumors that recapitulate clinically relevant characteristics of human HCC utilizing the Oncopig cancer model (capable of forming tumors through induced KRASG12D and TP53R167H expression). Here, we demonstrate our ability to develop Oncopig HCC cell lines with differential therapeutic susceptibilities through introduction of clinically relevant HCC driver mutations (PTENKO, AXIN1KO, or ARID1KO) via CRISPR-Cas9 gene editing. Specifically, we demonstrate that PTENKO increases susceptibility to PI3K inhibitors currently in clinical trials for treatment of PTEN null HCC and other cancer types. Therapeutic susceptibility of the established Oncopig WT, PTENKO, AXIN1KO, and ARID1KO HCC cell lines was assessed for PI3K inhibitors (GSK2636771, BAY 80-6946, and BKM120). Consistent with human studies, Oncopig PTENKO HCC cell lines displayed significantly increased sensitivity to GSK2636771 and BAY 80-6946, but not BKM120, compared to WT and PI3K inhibitor non-responsive AXIN1KO and ARID1AKO cells (see Table). In addition, Oncopig PTENKO HCC cells possessed significantly increased proliferation and migration rates compared to WT Oncopig HCC cells (1.6 and 2.8 fold, respectively; p &amp;lt; 0.01). These results validate the utility of the Oncopig HCC model for preclinical evaluation of novel targeted therapeutics in vitro. Future work demonstrating consistent results in vivo will enable the genetically defined Oncopig HCC model to be an ideal animal system to test precision medicine therapeutics prior to entry into the clinic. Citation Format: Mahmoud Khalafalla, Navin Viswakarma, Lobna Elkhadragy, Theresa K. Kelly, Mark Eccleston, Lawrence B. Schook, Ron C. Gaba, Kyle M. Schachtschneider. Validation of genetically defined Oncopig hepatocellular carcinoma cell lines for in vitro evaluation of targeted therapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5169.