tbuckley/cabot-search huggingface dataset:
Abstract 6821: The anticancer effects of polyisoprenylated phosphonyl ester inhibitors (PPEIs) of PMPMEase in pancreatic cancer cells
Authors: Jahnissi Odoom, Amarender Burra, Kweku Ofosu-Asante, Justin Mensah-Mamfo, Joshua Ablordeppey, Nazarius Lamango
Journal: Cancer Research (2025)

Abstract Monomeric G-proteins such KRAS, CDC42, RHOA, and RAC1 are polyisoprenylated and methylated to become fully functional. Polyisoprenylated protein methyl transferase (PPMTase) and polyisoprenylated methylated protein methyl esterase (PMPMEase) appear to regulate G-protein function. Previous studies showed that PMPMEase inhibition causes cancer cell death. In the current study, polyisoprenylated phosphonyl ester inhibitors (PPEIs) were developed as t, t, -farnesyl-targeted irreversible PMPMEase inhibitors. Experiments were conducted with two pancreatic cancer cell lines, MIA PaCa-2 and PANC-1. NSL-AB-01, NSL-AB-02, and NSL-AB-03 suppressed pancreatic MIA PaCa-2 cells cancer cell viability with EC50 values of 4.5, 4.8, and 4.6 µM, respectively, and 5.0, 6.4, and 5.1 µM for PANC-1 cells, respectively. Proliferation was inhibited by 99% and 95% for MIA PaCa-2 and PANC-1 cells at low micromolar PPEIs concentrations, respectively. PPEIs induced caspase activity by over 150% for both cell lines. Phosphorylation of MAPK proteins ERK1/2, MEK1/2, and CRAF were reduced by 77%, 50%, and 42% for MIA PaCa-2 cells, respectively. In PANC-1 cells, ERK1/2 phosphorylation decreased by 75%, while MEK1/2 increased by 140%. The PI3K/AKT proteins, S6 Kinase, PI3K, and AKT, were activated through phosphorylation by 19, 20, and 94%, in MIA PaCa-2 cells. However, opposing effects were observed in PANC-1 cells whereby PDK1 and PI3K phosphorylation were significantly decreased by 30 and 40%, respectively. PPEIs treatment caused actin filaments to become diffused, retracted, and clustered, causing the cancer cells to lose shape and become rounded. These findings show the potential role of PPEIs in disrupting cancer cell proliferation and, consequently, cancer progression. Citation Format: Jahnissi Odoom, Amarender Burra, Kweku Ofosu-Asante, Justin Mensah-Mamfo, Joshua Ablordeppey, Nazarius Lamango. The anticancer effects of polyisoprenylated phosphonyl ester inhibitors (PPEIs) of PMPMEase in pancreatic cancer cells [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 6821.
Abstract 3640: Mapping drug-gene interactions in cancer with large language models
Authors: Ying-Ju Lai, Li-Ju Wang, Yufei Huang, Yu-Chiao Chiu
Journal: Cancer Research (2025)

Abstract Understanding drug-gene relationships is critical for advancing targeted cancer therapies, identifying opportunities for drug repurposing, and improving patient outcomes. However, the vast and growing volume of biomedical literature presents significant challenges for researchers attempting to efficiently extract relevant insights. To address this, we developed an automated pipeline that integrates state-of-the-art large language models (LLMs) with up-to-date literature to reliably infer drug-gene interactions. By seamlessly interfacing PubMed with LLMs, the pipeline generates efficient, evidence-based inferences, effectively overcoming the limitations of static LLMs, including outdated knowledge and the potential for inaccurate conclusions. We systematically validated the pipeline using curated collections of drug-gene pairs from established knowledgebases. Comparative performance evaluations of various LLMs, including GPT-4o (OpenAI), Gemini 1.5 Pro (Google), and several open-source models, revealed that GPT-4o slightly outperformed Gemini 1.5 Pro, with both achieving an area under the ROC curve (AUROC) exceeding 90%. These proprietary models demonstrated substantial performance advantages over open-source alternatives. Using this pipeline, we analyzed hundreds of key oncogenes and FDA-approved drugs to construct a comprehensive pan-cancer drug-gene interaction network. This network identifies therapeutic targets and drug repurposing opportunities. The highest density of drug-gene pairs was observed in breast, colorectal, and lung cancers, reflecting significant therapeutic development and research interest in these prevalent cancer types. Additionally, our analysis of liver cancer, the third leading cause of cancer-related deaths worldwide, uncovered intricate multi-target effects of approved drugs such as sorafenib and lenvatinib. Beyond cancer-type-specific findings, the analysis also revealed numerous drug-gene associations spanning multiple cancer types. In summary, our pipeline integrates real-time literature retrieval with advanced LLMs and offers a robust and accessible resource for anti-cancer drug development. Designed with user accessibility in mind, the pipeline has the potential to enable cancer researchers to analyze drug-gene relationships without requiring programming expertise or extensive computational resources. This work provides a foundation for advancing therapeutic exploration and supporting innovation in oncology. Citation Format: Ying-Ju Lai, Li-Ju Wang, Yufei Huang, Yu-Chiao Chiu. Mapping drug-gene interactions in cancer with large language models [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 3640.
Abstract 4729: The reversible and selective FGFR2/3 inhibitor CGT4859 has superior target coverage of resistance mutations missed by leading FGFR inhibitors
Authors: John Fischer, Karyn Bouhana, Richard Brizendine, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Keith Koch, Erika Koslov-Davino, Macedonio J. Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou
Journal: Cancer Research (2025)

Abstract FGFR2 and FGFR3 alterations are oncogenic events across many solid tumors, often through chromosomal fusion or activating mutations. FGFR2 translocations are prevalent in intrahepatic cholangiocarcinoma, while FGFR3 mutations and fusions are prevalent in bladder cancer. Both indications have approved pan-FGFR inhibitors that demonstrate responses in patients that harbor these genetic alterations, however, responses are short-lived or show reduced activity in patients with on-target resistance mutations. In addition, efficacy of these agents has been hampered by inhibition of FGFR1, which leads to dose-limiting hyperphosphatemia. To address these issues, we present our clinical candidate CGT4859, a novel reversible FGFR2/3 inhibitor with activity against clinically relevant mutations and &amp;gt;140-fold selectivity over FGFR1. In vivo characterization of CGT4859 demonstrates robust efficacy in target-altered models at tolerated doses. Together, these data demonstrate CGT4859 as a potential best-in-class FGFR1-sparing pan-mutant FGFR2/3 inhibitor. Citation Format: John Fischer, Karyn Bouhana, Richard Brizendine, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Keith Koch, Erika Koslov-Davino, Macedonio J. Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou. The reversible and selective FGFR2/3 inhibitor CGT4859 has superior target coverage of resistance mutations missed by leading FGFR inhibitors [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 4729.
Abstract 6826: PRMT5 inhibition is a promising therapeutic strategy for high-risk neuroblastoma
Authors: Parul Suri, Saurabh Agarwal
Journal: Cancer Research (2025)

Abstract Neuroblastoma (NB), a pediatric solid tumor originating from the extracranial sympathetic nervous system, frequently persists as a metastatic, drug-resistant cancer despite recent improvements in dose-intensive chemotherapy, radiation, and surgical approaches. Identifying novel molecular targets and developing effective therapeutic regimens for NB is crucial. PRMT5, an arginine methyltransferase, has emerged as a potential target, with its inhibition demonstrating therapeutic effects in various cancer models. Multiple potent, small-molecule PRMT5 inhibitors are currently in clinical trials or development. In this study, we investigated the pre-clinical effects of a specific PRMT5 targeting small molecule inhibitor, PM5i, on NB growth. Analysis of multiple NB patient datasets revealed an inverse relationship between PRMT5 expression and NB patients' overall survival, underscoring PRMT5 as a potential therapeutic target. Our cytotoxicity and clonogenic assay data demonstrate that PM5i significantly inhibits NB proliferation and colony formation in a dose-dependent manner with IC50 values ranging from 1 to 4 µM across different NB cell lines (p&amp;lt;0.01). PRMT5 inhibition by PM5i significantly induced apoptosis with a 2-fold increase in Annexin V-positive cells compared to controls (p&amp;lt;0.05) and inhibited cell cycle progression by arresting cells in the S phase with the percentage of cells in the S phase increasing from 22% in controls to 45-50% in treated cells (p&amp;lt;0.01). These effects were consistent across different NB cell lines. To recapitulate in vivo tumor growth, we employed 3D spheroid models of NB. PM5i treatment significantly inhibited 3D spheroid growth and volume in a dose-dependent manner with about a 2-fold reduction compared to control treatments (p&amp;lt;0.01). Molecular analysis revealed that PM5i treatment downregulated the expression of genes involved in critical cell processes by 2 to 3-fold, including AKT, MAPK, and MYCN pathways in NB cells. These pathways are known to play crucial roles in NB pathogenesis and progression. Collectively, our data provide compelling evidence that PRMT5 targeting represents an effective therapeutic strategy for high-risk NB. The potent effects of PM5i on NB cell growth, survival, and key oncogenic pathways highlight the potential of PRMT5 inhibitors in NB treatment. Further development of PRMT5 inhibition strategies and their combination with current chemotherapies may pave the way for efficient clinical translation, holding significant promise for improving outcomes in high-risk NB patients. Citation Format: Parul Suri, Saurabh Agarwal. PRMT5 inhibition is a promising therapeutic strategy for high-risk neuroblastoma [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 6826.
Abstract 6142: Functional reprogramming of neutrophils in the tumor microenvironment
Authors: Filippo Veglia, Alessio Ugolini, Alessandra De Leo
Journal: Cancer Research (2025)

Abstract Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcome in cancer, including brain tumors. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and poor response to immunotherapy. However, the mechanisms underlying the regulatory reprogramming of neutrophils remain elusive. Here, we report that neutrophils suppress T cell function in mouse and human brain tumor tissues, contrasting with their non-immunosuppressive phenotype in the periphery. The immunosuppressive ability of brain-tumor infiltrating neutrophils was restricted to a subset of highly glycolytic neutrophils expressing the transferrin receptor CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+ neutrophils, which was accompanied by high avidity for glucose and production of lactate. Intracellular lactate caused lactylation of histone lysine residues that directly regulated the expression of arginase 1 (ARG1), required for T cell suppression. Pharmacological inhibition of glycolysis, lactate production or the histone lactylation writer CBP/P300, impaired histone lactylation and the expression of ARG1 and, accordingly, reduced the immunosuppressive activity of CD71+ neutrophils. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked the immunosuppressive ability of CD71+ neutrophils, delayed tumor progression and sensitized brain tumors to immunotherapy. Furthermore, a distinctive gene signature characterizing immunosuppressive and glycolytic CD71+ neutrophils correlated with adverse clinical outcomes across diverse human malignancies. Thus, our study identifies hypoxia-driven histone lactylation as a critical determinant of the functional reprogramming of neutrophils within tumors, providing a potential therapeutic strategy to counteract neutrophil-induced immunosuppression. Citation Format: Filippo Veglia, Alessio Ugolini, Alessandra De Leo. Functional reprogramming of neutrophils in the tumor microenvironment [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 6142.
Abstract 6824: Efficacy and mechanism of surufatinib combination with PD-1 monoclonal antibody and chemotherapy for the treatment of pancreatic cancer with liver metastasis in animal models
Authors: Mengjiao Fan, Ru Jia, Guanghai Dai
Journal: Cancer Research (2025)

Abstract Background: The phase 1b/2 study of surufatinib plus camrelizumab, nab-paclitaxel and S-1 (NASCA) as first-line therapy has demonstrated superior clinical efficacy compared with nab-paclitaxel and gemcitabine (AG) for metastatic pancreatic adenocarcinoma (PDAC) (NCT05218889), especially in patients with liver metastasis (LM). To delve deeper into the underlying mechanism behind NASCA's effectiveness in the LM group, we conducted animal experiments and utilized multiplex immunohistochemistry (mIHC) technology. Methods: Two animal models of pancreatic cancer (subcutaneous and LM) were established using KPC cells in C57BL/6 mice. The animals were then randomly assigned to receive placebo, AG, NASCA, and PD-1 plus nab-paclitaxel and S-1 (AS). Human primary pancreatic lesions (PL) and LM lesions were collected, and organ-specific differences were analyzed by using mIHC. Results: LM changes the effectiveness of NASCA in mice. NASCA outperformed than AG in subcutaneous model. In subcutaneous and LM model, NASCA and AG showed the comparable tumor regression to placebo in subcutaneous tumor, but better than AG in liver tumor. NASCA boosts anti-tumor efficacy in LM by improving immunosuppressive microenvironment. Flow cytometry of peripheral tissues revealed reduced MDSC and PDL1+ macrophages infiltration (p &amp;lt; 0.05) and increased NK and activated T cells infiltration (p &amp;lt; 0.05) in liver tumors with NASCA. Treg infiltration decreased in both subcutaneous and liver tumors from early (d5) to late (d14) treatment time points. Higher fractions of Treg cells were infiltrated in LM than PL by mIHC: A total of 59 patients with PDAC were enrolled to evaluated the organ-specific response of NASCA therapy. MIHC detected significantly higher fractions of FOXP3+ cells in stroma of LM compared with PL (p &amp;lt; 0.05). Patients with CD68+CD163- (percent) and FOXP3+ (percent) in stroma may benefit more from NASCA regimen. Conclusion: LM could alter the efficacy of NASCA in KPC mice through improving immunosuppressive microenvironment. The heterogeneity of mIHC is limited in LM and PL, but patients with CD68+CD163- and FOXP3+ in the stroma may benefit more from NASCA regimen, which may contribute to developing precise immunotherapy strategies for PDAC patients with LM. Citation Format: Mengjiao Fan, Ru Jia, Guanghai Dai. Efficacy and mechanism of surufatinib combination with PD-1 monoclonal antibody and chemotherapy for the treatment of pancreatic cancer with liver metastasis in animal models [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 6824.
Abstract 3970: Advancing multiple myeloma research: patient-derived 3D Organ-on-a-Chip models to reveal immunological mechanisms influencing cancer growth and resistance
Authors: Medbh A. Dillon, Kevin J. Lee, Cole G. Phalen, Aishwarya Chander, Imran McGrath, Love Tӓtting, Troy R. Torgerson, Melinda L. Angus-Hill
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) is characterized by malignant plasma cells infiltrating the bone marrow. The standard induction therapy for MM includes combining bortezomib, lenalidomide and dexamethasone (VRd); this has recently expanded to include an anti-CD38 antibody, which has improved patient outcomes. Despite the recent advances in treatment, patients with MM commonly relapse and it is a disease that remains ultimately incurable. More advanced patient-derived 3D models would allow a greater understanding of the tumor microenvironment (TME) and how it changes during treatment. This is needed for the identification and validation of new biomarkers for this disease and could aid in predicting individual treatment responses. Longitudinal Olink proteomic data, generated by our group, from the plasma and bone marrow interstitial fluid (BMIF) of patients undergoing VRd induction therapy, allowed us to glean key insights into the changes specific to the bone marrow tumor microenvironment (TME) throughout therapy that can be validated in our 3D MM model system. Our longitudinal data shows elevated interleukin 16 (IL-16) in the BMIF of patients at diagnosis, which decreases following induction therapy. IL-16 is a proinflammatory cytokine that acts as a chemoattractant for CD4+ T cells, myeloid cells and eosinophils, and has also been shown to be essential for proliferation of MM cell lines. Extracellular IL-16 may contribute to tumor growth or influence immune cell recruitment to the bone marrow TME. Its increased presence in the BMIF compared to the plasma suggests a localized role within the bone marrow TME. To further investigate the role of IL-16 in the MM TME we developed a novel, patient-derived organ-on-a-chip model of multiple myeloma bone marrow. Using bone marrow mononuclear cells (BMMC) and donor matched bone marrow stromal cells (BMSC) we developed a complex TME on-chip using primary human cells. Using this model we examined the role of IL-16 and other differentially expressed growth factors on tumor development, hematopoietic stem cell differentiation and cytokine production in the TME. Preliminary data shows an increase in proliferation of malignant MM cells in the presence of IL-16, highlighting IL-16 as a potentially promising therapeutic target. Citation Format: Medbh A. Dillon, Kevin J. Lee, Cole G. Phalen, Aishwarya Chander, Imran McGrath, Love Tӓtting, Troy R. Torgerson, Melinda L. Angus-Hill. Advancing multiple myeloma research: patient-derived 3D Organ-on-a-Chip models to reveal immunological mechanisms influencing cancer growth and resistance [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 3970.
Abstract 7101: Envisioning leadership for Latino cancer health equity in prevention and control
Authors: Rolando Francisco Trejos, Karen Liller
Journal: Cancer Research (2025)

Abstract Background: Latinos are the second-largest ethnic population in the United States of America (USA), and although their cancer rates, for most cancer types, have significantly decreased over the last decade, Latino cancer inequities and disparities continue to result in late cancer diagnosis, cancer treatment-related burden, cancer-related complications, and poor quality of life. Leadership training and skills are needed to adequately prepare healthcare professionals to respond to the complex and ever-evolving nature of cancer inequities. Therefore, this presentation will evaluate current curricular offerings discussing leadership and/or health equity to provide evidence-based recommendations to inform future clinical and community-based curricular and educational approaches. Methods: We reviewed multiple trainings and educational opportunities currently offered in the USA that discussed or included leadership and/or health equity components and a focus on cancer. Programs were evaluated to understand current gaps in leadership training and the relevance of competency-based education as an effective curriculum development approach to inform the development of future curricular offerings. The literature on leadership for health equity in cancer among Latinos was summarized using the PubMed, Embase (Elsevier), and Scopus (Elsevier) databases following the PRISMA guidelines. Results: The existing programs in the evidence included the Cancer 101, Éxito Latino Cancer Research Leadership Training, Redes en Acción, and Minority Training in Cancer Control Research programs. Results suggest the importance of developing, implementing, and evaluating formal and informal training programs on leadership that can equip healthcare professionals to respond to the complex and ever-evolving nature of Latino cancer inequities. Most programs included post-baccalaureate youth interested in doctoral-level training. However, absent from the identified curricular offerings are capacity-building training and leadership training, as well as skills that would enable researchers and cancer care providers with the necessary tools to become advocates and patient-driven supporters of patients plagued by cancer and cancer care-related disenfranchisement. Discussion and Conclusion: Leadership education efforts to tackle Latino cancer inequities are necessary to ensure responding to the unique and complex needs and realities of Latinos in the USA, which can inform clinical and community-based initiatives recognizing the historical and intergenerational factors that shape Latino health. Citation Format: Rolando Francisco Trejos, Karen Liller. Envisioning leadership for Latino cancer health equity in prevention and control [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 7101.