tbuckley/cabot-search huggingface dataset:
Abstract 1408: CSTF2-induced alternative polyadenylation of GPC3 RNA contributes to hepatocellular carcinoma
Authors: Suk Woo Nam, Soyoung Jeon, Sang Yean Kim, Min Jeong Na, Jin Woong Ha
Journal: Cancer Research (2025)

Abstract Alternative polyadenylation (APA) involves the addition of a polyadenylate (poly-A) tail to the 3' end of an mRNA molecule, which is essential for mRNA stability and translation into proteins. This mechanism is critical for gene expression and function, particularly in cancer. Glypican-3 (GPC3) is significantly overexpressed in hepatocellular carcinoma (HCC) and is associated with poor prognosis. APA profiling analysis showed that the 3’ UTR of GPC3 is shortened, which strongly correlates with increased GPC3 expression in HCC. Disruption of GPC3 led to inhibited cellular growth and increased apoptotic cell death in HCC cells, while ectopic overexpression of a GPC3 plasmid stimulated growth and proliferation in these cells. Furthermore, Cleavage Stimulation Factor Subunit 2 (CSTF2), a component of the cleavage stimulation factor complex, was found to promote the shortening of GPC3's 3' UTR through APA regulation in HCC cells. CSTF2 expression also correlated with GPC3 levels and the dPDUI (Percentage of Distal PolyA Site Usage Index) of GPC3 in HCC. Knockdown of CSTF2 resulted in decreased GPC3 expression, which inhibited cell growth and proliferation while increasing apoptotic cell death in HCC cells. Additionally, CSTF2 knockdown led to lengthening of the GPC3 3’ UTR, whereas overexpression of CSTF2 shows the opposite effect. Using predictive analysis with online tools TargetScan, miRDB, and miRabel, 40 miRNAs were identified as potential binders to the GPC3 3’ UTR. In vitro functional analysis demonstrated that miR-96-5p and miR-140-5p sustain the normal expression of GPC3 in hepatocytes, and that the shortening of the 3’ UTR of GPC3 RNA contributes to hepatocarcinogenesis. Overall, these findings suggest that the aberrant overexpression of GPC3, driven by selective APA regulation mediated by CSTF2, contributes to the malignant transformation and growth of hepatocytes, providing a novel therapeutic target for liver malignancies. Citation Format: Suk Woo Nam, Soyoung Jeon, Sang Yean Kim, Min Jeong Na, Jin Woong Ha. CSTF2-induced alternative polyadenylation of GPC3 RNA contributes to hepatocellular carcinoma [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 1408.
Abstract 1528: JAG1-driven macropinocytosis as a critical regulator of nutrient scavenging and tumor progression in pancreatic cancer
Authors: Mofei Huang, Bingqing Zou, Yimin Ma, Wei Xin, Lan Zhou
Journal: Cancer Research (2025)

Pancreatic cancer (PanCan), known for its aggressive nature, poor prognosis and often resistant to therapeutics, remains a major global health burden (Conroy, Desseigne et al. 2011, Von Hoff, Ervin et al. 2013, Howlader N 2021, Bray, Laversanne et al. 2024). Exploring new therapeutic targets is urgent. Studies have reported that PanCan cells undergo metabolic reprogramming in response to oncogenic signals for survival and tumor progression. Macropinocytosis, as an important nutrient scavenging metabolic pathway, fuels KRAS-driven PanCan cell growth, especially under nutrient-deficient condition (Ramirez, Hauser et al. 2019). The Notch signaling pathway is pivotal in PanCan initiation and development (Miyamoto, Maitra et al. 2003, Thomas, Zhang et al. 2014). Here, we demonstrated that Jagged-1 (JAG1) is the predominant Notch ligand expressed in human PanCan tissues and patient-derived xenografts, but only weakly presented in endothelial cells of normal pancreas. Elevated JAG1 gene expression is associated with worse survival in TCGA PanCan patient cohort, implicating that JAG1 is a prognostic marker for PanCan. However, whether JAG1-driven Notching signaling affects PanCan cellular metabolism remains poorly understood. Preliminary RNA-seq analysis on JAG1-depleting KPC tumor lines shows deactivated pathways activities, including “PI3k-AKT-mTOR”, “positive regulation of endocytosis” and “actin cytoskeleton organization”, all of which are important molecular events for macropinocytosis processes. We further investigated and noticed decreased dextran-TMR uptake capacities in those JAG1-depleting KPC cells, indicating attenuated macropinocytic activity upon JAG1 extinction. Along this line, the widely targeted metabolomics assay revealed peptides and amino acids as the most abundant metabolite family with significant reduction in JAG1-depleting KPC tumor cells. Finally, JAG1 ablation decreased KPC cell proliferation and spheroid forming efficiency in vitro. In addition, JAG1 deletion reduced tumor growth in syngeneic subcutaneous KPC mouse models (6419C5, 7160C2 and 6422C5) as well as in a KPC orthotopic model (6419C5). Collectively, our findings suggest JAG1 as a key driver of macropinocytosis in PanCan cells and imply the potential of JAG1 ablation to inhibit nutrient scavenging and tumor progression. Citation Format: Mofei Huang, Bingqing Zou, Yimin Ma, Wei Xin, Lan Zhou. JAG1-driven macropinocytosis as a critical regulator of nutrient scavenging and tumor progression in pancreatic 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 1528.
Abstract 5571: Identifying and targeting novel kinase regulators for cancer metastasis
Authors: Wenliang Li
Journal: Cancer Research (2025)

Abstract Background: Metastasis is responsible for &amp;gt;90% of cancer death. However, metastasis is still poorly understood and the current approaches to prevent or treat human metastatic cancers are largely unsuccessful. Methods and Results: Through RNAi and cDNA functional screening, genomics analysis, and functional validations, we have identified several critical but previously unknown/understudied kinase regulators for metastasis. As an example, shRNA screening revealed that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in the aggressive variant of prostate cancers, so called treatment-related neuroendocrine prostate cancer (NEPC). We further found that GRK3 is a key missing link between two prominent phenotypes of NEPC, i.e. angiogenesis and neuroendocrine feature. Mechanistically, GRK3 phosphorylates histone deacetylase 2 (HDAC2) at S394 and enhances HDAC2’s epigenetic activity. Through compound library screening, we have identified several compounds that block the kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could significantly inhibit NEPC cell growth in culture and in mouse xenografts. Another group of potential metastasis regulators we identified are new EMT-regulating kinases from our kinome cDNA screening for epithelial-mesenchymal transition (EMT). For example, mixed lineage kinase ZAK positively regulates EMT phenotypes and migration of cancer cells in culture, as well as metastasis in mice. ZAK overexpression correlates with poor prognosis in cancer patients. We are carrying out in silicon docking analysis and chemical genomics to identify potent and specific inhibitors for ZAK as research tools and drug candidates for metastatic cancers. Conclusions: Our robust and unbiased functional screening has identified several novel kinase regulators and potential drug targets for cancer metastasis. For example, GRK3 has emerged as a critical kinase for metastatic prostate cancer cells and a key regulator of aggressive neuroendocrine prostate cancer phenotypes, while ZAK has been identified as a potent new regulator of epithelial-to-mesenchymal transition (EMT). Citation Format: Wenliang Li. Identifying and targeting novel kinase regulators for cancer 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 5571.
Abstract 5412: Developing combination therapies for telomerase-overexpressing cancers
Authors: Vincent Maranda, Frederick S. Vizeacoumar, Yue Zhang, Liliia Kyrylenko, Andrew Freywald, Franco J. Vizeacoumar
Journal: Cancer Research (2025)

Abstract Cancer heterogeneity poses a significant medical challenge, necessitating therapies tailored not only to individual patients but also to the unique cancer clones that exist within diverse microenvironmental contexts. Despite this diversity, nearly all cancer cells share a reliance on telomeres to maintain genomic stability. The telomerase (hTERT) gene is hyperactive in many cancers and has been identified as a potential target for treatment. While this has led to the development of multiple telomerase-targeting approaches, disappointingly, none have been approved in clinical applications yet. To circumvent this concern, our team has applied a genetic approach called synthetic dosage lethality (SDL), to exploit hTERT overexpression to identify potential targets to treat cancer. SDL is a genetic concept, where a normally non-lethal gene inactivation kills cells only in the context of overexpression of another gene like hTERT. Our laboratories have used lentiviral-based pooled CRISPR/Cas9 and pooled shRNA-screening platforms to systematically query the genome and recently identified several SDL partners of hTERT. Through extensive validation using pooled in vivo CRISPR/Cas9 screens across multiple cell lines, tumor xenografts, and patient-derived organoids, we identified RMT1, an RNA 2'-O-methyltransferase, as a prominent SDL partner of hTERT. In collaboration with the AtomWise and Thoth Biosimulations companies, we have developed novel inhibitors for RMT1 that preferentially suppress hTERT-overexpressing cell lines growth and viability. We have also performed a large-scale screen of FDA-approved small molecule inhibitors with the goal of repurposing these drugs to target hTERT-overexpressing cancers. Subsequently, we plan to apply these therapies in combination to amplify the efficiency of treatment against cancers, yielding preclinical evidence to support the development of novel cancer therapies. Since hTERT activity is essential in all cancer cells, our findings introduce a transformative approach to overcoming cancer cell heterogeneity by targeting the SDL interactions of hTERT. This strategy also capitalizes on the ubiquitous overexpression of hTERT in all cancer types, enabling the selective eradication of hTERT-dependent malignancies. Citation Format: Vincent Maranda, Frederick S. Vizeacoumar, Yue Zhang, Liliia Kyrylenko, Andrew Freywald, Franco J. Vizeacoumar. Developing combination therapies for telomerase-overexpressing cancers [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 5412.
Abstract 1625: Redox homeostasis is a therapeutic vulnerability in lethal neuroendocrine prostate cancer
Authors: Mu-En Wang, Wei-Ling Tu, Ji-Hoon Kim, Yi Lu, Alyssa Bawcom, Andrew J. Armstrong, Qianben Wang, Yuzhuo Wang, Jiaoti Huang, Ming Chen
Journal: Cancer Research (2025)

Abstract Background: Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer that often develops after second-generation anti-androgen therapies. The current treatment options for NEPC are limited and only produce disappointing results, highlighting the urgent need for novel therapies. Previously, we have found that NEPC cells are vulnerable to BCL2 and GPX4 inhibitors compared to their counterparts, prostate adenocarcinoma (PADC). Here, we aim to determine whether and how combining BCL2 and GPX4 inhibitors would enable optimal therapeutic effects in NEPC. Methods: We conducted drug synergism analyses of BCL2 and GPX4 inhibitors using NEPC cell lines and determined their impacts on the major cell death pathways by performing rescuing experiments. To further determine the molecular mechanisms of BCL2 and GPX4 inhibitors-induced cell death in NEPC, we measured the intracellular reactive oxygen species (ROS) levels and tested the rescuing effects of various antioxidants and reducing agents on cell death. Finally, we determined the in vivo therapeutic efficacy of BCL2 and GPX4 inhibitors in an NCI-H660 cell line-derived xenograft (CDX) tumor model. Results: Our results demonstrate that the BCL2 inhibitor ABT-199 and GPX4 inhibitor C18 synergistically induced apoptosis in NEPC cell lines in a ROS-independent manner. Although N-acetylcysteine (NAC) rescued ABT-199 and C18 cotreatment-induced apoptosis, the CellROX Green assay revealed no significant changes in ROS levels in ABT-199 and C18-cotreated cells. Surprisingly, reducing agents including tris(2-carboxyethyl)phosphine (TCEP) and Dithiothreitol (DTT) strongly rescued cell death induced by ABT-199 and C18 cotreatment. Our findings therefore suggested that the cell-killing effects of ABT-199 and C18 were due to ROS-independent disruption of redox homeostasis. Lastly, our preclinical tumor study showed that the ABT-199 and C18 combinatorial therapy significantly suppressed the tumor growth of NEPC. Conclusions: Our study validated the combination of BCL2 and GPX4 inhibitors as a feasible approach for the treatment of NEPC and suggested that redox homeostasis is a therapeutic vulnerability in NEPC. Citation Format: Mu-En Wang, Wei-Ling Tu, Ji-Hoon Kim, Yi Lu, Alyssa Bawcom, Andrew J. Armstrong, Qianben Wang, Yuzhuo Wang, Jiaoti Huang, Ming Chen. Redox homeostasis is a therapeutic vulnerability in lethal neuroendocrine prostate 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 1625.
Abstract 3313: GenialisTM Supermodel: A large molecular model enabling monotherapy and combination therapy selection in KRAS-mutated cancers
Authors: Josh Wheeler, Luka Ausec, Miha Štajdohar, Rafael Rosengarten, Mark Uhlik
Journal: Cancer Research (2025)

Abstract KRAS mutations drive approximately 25% of human cancers, resulting in 3.9 million new cases annually. Recently approved KRAS inhibition (KRASi) monotherapies demonstrate limited efficacy and durability. Diverse combination therapies are under investigation. This necessitates biomarker strategies for identifying patients most likely to respond to KRASi monotherapy or combination therapy.The Genialis™ Supermodel is a foundation model of cancer biology that can be used to derive novel biomarkers for diagnosis, clinical development, and treatment decision-making in oncology. Trained on nearly 1 million harmonized transcriptomic samples, this large molecular model (LMM) maps individual patient RNA-seq samples into biologically meaningful spaces defined by distinct combinations of biological signatures. Each biological subspace reflects mechanisms relevant to a specific therapeutic class. These mappings enable the selection of core biological features, which are then used in downstream machine-learning models to predict therapeutic response and stratify patients.The Supermodel captures biology linked to responses to KRASi, EGFR inhibitors, ICI (immune checkpoint inhibitors), and standard-of-care chemotherapy, among other therapeutic mechanisms, generating classifiers that predict monotherapy responses in diverse preclinical and clinical cohorts. We further demonstrate that the intersection of these individual classifiers identifies clinical contexts where monotherapy is sufficient and where combination therapies may provide additional benefit. These results refine patient stratification and guide clinical decision-making by aligning treatment selection with the underlying tumor biology and therapeutic context.The Genialis™ Supermodel establishes a novel and robust framework for precision oncology, enhancing patient stratification, optimizing clinical decision-making, and expanding opportunities for effective KRAS-driven cancer treatments. Citation Format: Josh Wheeler, Luka Ausec, Miha Štajdohar, Rafael Rosengarten, Mark Uhlik. GenialisTM Supermodel: A large molecular model enabling monotherapy and combination therapy selection in KRAS-mutated cancers [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 3313.
Abstract 4277: EP601: Agonism of GPR84 activates myeloid cells and augments the response to anti-CTLA4 to promote tumor growth inhibition and prolong survival in a syngeneic (CT26) tumor model
Authors: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Sarah Rorive, Guillaume Dutheuil
Journal: Cancer Research (2025)

Abstract GPR84 is a G-protein coupled receptor predominantly expressed on myeloid cells such as macrophages, NK cells, monocytes and neutrophils. It has previously been reported that GPR84 expression is induced by acute inflammatory stimuli and furthermore that GPR84 may be an interesting target to reverse the immunosuppressive tumor microenvironment1. In the current study, induced expression of GPR84 is confirmed as it is demonstrated that there is a 5-fold (or greater) expression of GPR84 on human (M1) macrophages polarized with either IFN-gamma or muramyl dipeptide-and-LPS (“MDP+LPS”). Compound A (CpdA) is a proprietary, selective, small-molecule agonist at GPR84 with similar potency at both the human and mouse GPR84 receptor orthologs (cAMP assay, EC50 = 13 nM and 9 nM, respectively). CpdA promotes TNF-alpha secretion from MDP+LPS-activated human macrophages in a concentration-dependent manner and this response is blocked by the GPR84 antagonist GLPG1205. The pharmacokinetic profile of CpdA has been established in rodents (t1/2 = 1h, oral bioavailability = 25%) and the compound is appropriate for in vivo testing. In the CT26 mouse tumor model, CpdA (30 mg/kg, PO, BID) significantly increased the response to anti-CLTA4 (2 mg/kg, IP, BIW) to &amp;gt;80% tumor growth inhibition and improved survival corresponding to altered immune cell infiltration into the tumor. These results demonstrate the potential of pharmacological activation of GPR84 as a novel approach relevant to cancer immunotherapy.1Li et al., Cancer Immunol Immunother (2024) Citation Format: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Sarah Rorive, Guillaume Dutheuil. EP601: Agonism of GPR84 activates myeloid cells and augments the response to anti-CTLA4 to promote tumor growth inhibition and prolong survival in a syngeneic (CT26) tumor model [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 4277.
Abstract 3338: A CpG methylation based epigenetic signature for recurrence prediction in stage II/III colorectal cancer: <i>The CENSURE Study</i>
Authors: Caiming Xu, Silei Xu, Joan Maurel, Man Li, Ajay Goel
Journal: Cancer Research (2025)

Introduction: Adjuvant chemotherapy (ACT) is the standard of care for patients with stage III or high-risk stage II colorectal cancer (CRC) following curative-intent resection. However, over 30% of these patients experience recurrence despite treatment, highlighting the urgent need for developing predictive biomarkers of response to ACT. This study sought to identify epigenetic biomarkers for predicting recurrence in stage II/III CRC. Patients and Methods: This study included three phases: discovery, training, independent testing. In the discovery phase, we performed genomewide methylation profiling analysis between recurrent (recurrence-free survival, RFS &amp;lt; 5 years) and non-recurrent patients with CRC. A LASSO-based machine learning algorithm was employed to refine and optimize the candidate CpG sites. Subsequently, we developed and tested a methylation biomarker panel by quantitative pyrosequencing assays, followed by eXtreme Gradient Boosting (XGB) machine-learning algorithm in both the training (n = 236) and testing (n = 175) cohorts. Finally, we established the CENSURE (CpG mEthylatioN-based epigenetic SignatURE) model, which combined the CpG methylation panel and carcinoembryonic antigen (CEA) levels, to predict recurrence in stage II/III CRC. Results: A panel of 8 CpG candidates identified in the discovery phase was refined to 6 using XGB in the training cohort. The 6-CpG panel demonstrated robust ability to predict recurrence, with AUC values of 91.2% and 79.3% in the training and testing cohorts, respectively. Multivariate Cox regression analysis revealed that CEA ≥ 5 ng/mL (HR 2.92; 95% CI: 1.81-4.70) and the CpG panel (HR 19.5; 95% CI: 8.78-43.1) were independent predictors of recurrence. Building on this, we developed the CENSURE model, which integrates the CpG panel with CEA. The CENSURE model achieved AUC values of 95.2% and 86.1%, with sensitivities of 83.9% and 83.3% in the training and testing cohorts, respectively. CENSURE high-risk patients exhibited significantly higher 5-year (71.5% vs 8.0%) and 2-year recurrent rates (48.0% vs 5.4%). Notably, the CENSURE model outperformed CEA risk stratification alone, correctly predicting an additional 46.5% (40 out of 86) of recurrence cases in the entire study cohort. Conclusions: In conclusion, the CENSURE assay represents a novel potential advance with a significant clinical impact for postoperative recurrence prediction in stage II/III CRC. Citation Format: Caiming Xu, Silei Xu, Joan Maurel, Man Li, Ajay Goel. A CpG methylation based epigenetic signature for recurrence prediction in stage II/III colorectal cancer: The CENSURE Study [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 3338.