tbuckley/cabot-search huggingface dataset:
Abstract 2212: Microbial metabolic pathways guide response to immune checkpoint blockade therapy
Authors: Iris L. Mimpen, Thomas W. Battaglia, Miguel Parra Martinez, Laurien J. Zeverijn, Birgit S. Geurts, Louisa R. Hoes, Vincent van der Noort, Hans Gelderblom, Krijn K. Dijkstra, Lodewyk F. Wessels, Emile E. Voest
Journal: Cancer Research (2025)

Abstract Recent studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. We hypothesized that community-level metabolic pathways across microbes are more suitable to predict ICB response. Using a curated resource of pan-cancer metagenomics data of ICB-treated patients, we identified several microbial metabolic processes significantly associated with response. Methylerythritol phosphate (MEP) pathway activity was associated with response and intratumoral Vδ2 T cell infiltration and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, the riboflavin pathway was associated with ICB resistance, and its intermediates led to mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Collectively, our results highlight the relevance and complexity of metabolite-mediated microbiome-immune crosstalk. Citation Format: Iris L. Mimpen, Thomas W. Battaglia, Miguel Parra Martinez, Laurien J. Zeverijn, Birgit S. Geurts, Louisa R. Hoes, Vincent van der Noort, Hans Gelderblom, Krijn K. Dijkstra, Lodewyk F. Wessels, Emile E. Voest. Microbial metabolic pathways guide response to immune checkpoint blockade therapy [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 2212.
Abstract 2649: Defining how Rnd3, a novel regulator of breast cancer invasion, affects the metastatic potential of triple-negative breast cancer
Authors: Noemi Garcia Garcia, Thanh Ha Vy Nguyen, Dane Richey, Katie R. Ryan
Journal: Cancer Research (2025)

Abstract The purpose of this study is to investigate whether the atypical Rho GTPase, Rnd3, affects triple-negative breast cancer (TNBC) cells metastatic potential (invasion and migration rates). One of the most dangerous attributes of cancer is its ability to metastasize and spread. The 5-year survival rate for localized breast cancer is 90%. However, this drops to 29% when breast cancer metastasizes. Identifying key regulatory proteins and signaling pathways involved in cell migration and invasion, two hallmarks of metastasis, will pave the way to potential therapeutic targets for reducing the metastatic potential of breast cancer. Rho GTPases regulate cellular processes that are commonly dysregulated in cancer with many studies focusing on what roles these proteins play in tumorigenesis. The expression level of the atypical Rho GTPase, Rnd3, rather than Rnd3 mutations, has been linked to cancer. High expression of Rnd3 increases cellular migration and invasion in several cancers, while depletion of Rnd3 decreases cellular proliferation and migration. How Rnd3 expression affects breast cancer progression is unknown. Here we assayed a panel of TNBC cell lines and assessed their migration and invasion potential, we observed a correlation of high Rnd3 expression and high cell migration and invasion rates. After knocking down Rnd3 expression in these cell lines we observed a significant reduction in cell invasion in MB-231, HCC1937, and MCF7 cells, and decreased cell migration in MB-231 cells. Rnd3 has been shown to regulate cell migration via the RhoA-ROCK1 pathway in melanoma. We were unable to rescue invasion rates in Rnd3 knockdown MB-231 cells following either chemical inhibition or knockdown of ROCK1, indicating Rnd3 is regulation cell invasion via a novel pathway in TNBC cells. Our findings indicate that Rnd3 regulates cell invasion and migration, two hallmarks of metastasis, in TNBC cells. Citation Format: Noemi Garcia Garcia, Thanh Ha Vy Nguyen, Dane Richey, Katie R. Ryan. Defining how Rnd3, a novel regulator of breast cancer invasion, affects the metastatic potential of triple-negative breast 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 2649.
Abstract 1765: RPT1G, a first-in-class hyperbolic NAMPT inhibitor that avoids on-target toxicity
Authors: Gregory Thomas Crimmins, Min Wu, Timothy Jarvela, Yushma Bhurruth-Alcor, James Digel, Francis Roushar, Dexter Davis, Caroline M. Robb, Michael Schelle, Banumathi Cole, Frank McCormick, Dennise A. De Jesús-Díaz
Journal: Cancer Research (2025)

Abstract Therapeutic inhibition of NAD+ synthesis has been challenging to achieve in the clinic due to severe on-target toxicity stemming from the critical role of NAD+ in living systems. The elevated energy requirements of cancer cells necessitate increased NAD+ recycling through the nicotinamide phosphoribosyltransferase (NAMPT) salvage pathway. Drug candidates have attempted to reduce NAD+ in cancer cells by complete inhibition of NAMPT, resulting in systemic, dose-limiting toxicity. RPT1G is a first-in-class hyperbolic inhibitor that significantly reduces, but does not eliminate, NAMPT activity. This unique mechanism-of-action reduces NAD+ below survival thresholds in cancer cells while allowing survival of healthy tissues, manifest by limited on-target toxicity in GLP studies and robust therapeutic efficacy in multiple oncological models. RPT1G has been approved to start clinical testing in healthy volunteers. This first-in-human study will determine the safety and pharmacokinetics of hyperbolic NAMPT inhibition while measuring metabolic changes resulting from reduced NAMPT activity. RPT1G represents the first hyperbolic NAMPT inhibitor to be tested in humans, opening opportunities to therapeutically modulate NAD+ synthesis and providing a roadmap for the development of hyperbolic inhibitors of other essential enzyme targets. Citation Format: Gregory Thomas Crimmins, Min Wu, Timothy Jarvela, Yushma Bhurruth-Alcor, James Digel, Francis Roushar, Dexter Davis, Caroline M. Robb, Michael Schelle, Banumathi Cole, Frank McCormick, Dennise A. De Jesús-Díaz. RPT1G, a first-in-class hyperbolic NAMPT inhibitor that avoids on-target toxicity [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 1765.
Abstract 3643: AI driven discovery of novel synthetic lethal gene pairs for targeted cancer therapy
Authors: Amalia Soenens, Daniel Miller, Oliver Vipond, Florencia Skuras, Alfie Brennan, Anna Hercot
Journal: Cancer Research (2025)

Abstract Synthetic lethality (SL) offers a promising avenue for cancer therapy by exploiting vulnerabilities unique to tumor cells and minimizing off-target effects on normal tissue. However, the application of SL-based therapies remains constrained by a limited repertoire of validated targets and biomarkers. Using data from the Cancer Dependency Map (DepMap) and advanced in silico modeling, Evariste’s Frobenius Target platform identified 50 potential SL gene pairs with druggable nodes and rational mechanisms linking targets and biomarkers. From this set, 24 gene pairs were prioritized for validation based on translational relevance and impact on the patient population. Validation was achieved through a collaborative high-throughput workflow with EditCo Bio, leveraging their CRISPR-based cell line engineering platform to generate 72 knockout pools in under three weeks. Validation studies in multiple cell lines demonstrated &amp;gt;10 high-confidence SL pairs, including a novel SL relationship involving focal adhesion kinase (FAK). To further substantiate this relationship, novel inhibitors were developed with best-in-class selectivity over the SL partner gene. Functional assays confirmed these inhibitors’ effectiveness in biomarker-low cell lines, with promising implications for clinical translation. This study highlights the potential of AI-driven approaches to uncover the next generation of SL targets, expanding the therapeutic landscape in cancer research. By focusing on biomarker-low gene expression as a predictor of SL, our work establishes a robust framework for the discovery and validation of clinically actionable SL relationships. Citation Format: Amalia Soenens, Daniel Miller, Oliver Vipond, Florencia Skuras, Alfie Brennan, Anna Hercot. AI driven discovery of novel synthetic lethal gene pairs for targeted cancer therapy [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 3643.
Abstract 2935: Development of selective HER2 covalent inhibitors with brain penetration for effective treatment of CNS metastases
Authors: Hyunjin Park, Yu-Yon Kim, Jiyoung Jeon, Sun Young Jang, Young Gil Ahn, Haemin Chon
Journal: Cancer Research (2025)

Abstract HER2 alterations, including amplification, overexpression, and mutations, are implicated in the development and progression of brain metastases (BM) and leptomeningeal metastases (LM) across various cancer types. In breast cancer, BM occurs in 15-25% of patients, with up to 50% of HER2-positive cases developing BM, underscoring the importance of HER2 amplification in metastatic progression. Similarly, HER2 alterations are positively associated with a higher risk of LM, affecting up to 25% of HER2-positive metastatic breast cancer patients. Although HER2 alterations are less common in lung cancer and melanoma, the high incidence of BM (20-40% in lung cancer and up to 50% in melanoma) and LM (3-5% in lung cancer and up to 23% in melanoma) highlights the importance of targeting HER2-driven pathways to manage these aggressive metastatic complications. The role of HER2 mutation and amplification in promoting metastatic progression establishes its significance as both a biomarker and target for tailored therapies. BM and LM are associated with poor prognosis and significantly reduced overall survival. Therefore, effective management of BM and LM requires addressing HER2-driven mechanisms, highlighting the unmet need for selective HER2 inhibitors with brain-penetrating properties capable of targeting both HER2 mutants and HER2WT amplification in HER2-altered BM and LM. Herein, we report the development of potent and selective covalent HER2 inhibitors, the Hanmi compounds, which exhibit strong anti-tumor activity in BM and LM models with high selectivity over EGFRWT. The growth-inhibitory effects of these compounds were evaluated in vitro using cell lines harboring HER2G776insVG/C mutations and HER2WT amplifications. Additionally, their anti-tumor efficacy was assessed in BM and LM mouse models. Hanmi compounds significantly reduced tumor burden and markedly improved survival in mice intracranially implanted with HER2WT-amplified N87 cells. Moreover, in the H1781 LM model harboring HER2G776insVG/C mutations, these compounds demonstrated superior efficacy by significantly increasing median overall survival (mOS) and inhibiting tumor growth compared to the approved HER2 targeting agent. These findings highlight the potential of Hanmi compounds as effective treatments for central nervous system (CNS) metastases, including BM and LM, addressing a critical unmet need in the management of HER2-altered metastatic diseases. Citation Format: Hyunjin Park, Yu-Yon Kim, Jiyoung Jeon, Sun Young Jang, Young Gil Ahn, Haemin Chon. Development of selective HER2 covalent inhibitors with brain penetration for effective treatment of CNS metastases [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 2935.
Abstract 4585: Exploiting intrinsic bioelectrical signatures for label-free immune cell sorting
Authors: Dean E. Thomas, Ilyssa E. Ramos, Kyle S. Kinskie, Kyle M. Brown, James M. Cherry, Alexandra R. Hyler
Journal: Cancer Research (2025)

Abstract Immune cell separation from heterogeneous samples is crucial for various downstream research applications. Standard methods for cell purification are laborious and require additional fluorescent or magnetic labels to identify cells of interest. Approaches contingent upon the use of labels may interfere with downstream testing and analysis, like single cell sequencing or downstream oncology research. Label-free cell sorting by electrokinetic dielectrophoresis (DEP) has recently been used to characterize and separate target subpopulations from complex samples. Available literature describes the use of DEP for isolation and enrichment of limited cell types. However, technical challenges and uncertainty have restricted DEP's commercialization and widespread implementation for biological use. To address this pitfall, we have exploited the strength of the CytoR1 platform for label-free sorting of T-cells, B-cells, and monocytes from bulk sample preparations. Characterization and isolation of these cells will support the CytoR1 platform's capabilities. Variables like frequency, voltage, and flow rate are incorporated in the profiling of target cells, facilitating the development of custom workflows to enrich individual immune cell populations from heterogeneous samples without labels. Platform validation will involve downstream fluorescence-activated cell sorting (FACS) and potential RNA sequencing to confirm the accuracy of label-free sorting. Here, we introduce a workflow implementing a microfluidics-based, benchtop cell-sorting technology, the CytoR1, for precise enrichment and capture of unlabeled target cell populations. Citation Format: Dean E. Thomas, Ilyssa E. Ramos, Kyle S. Kinskie, Kyle M. Brown, James M. Cherry, Alexandra R. Hyler. Exploiting intrinsic bioelectrical signatures for label-free immune cell sorting [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 4585.
Abstract 3356: Construction of a 23-gene risk scoring system to predict disease recurrence and chemotherapy response in mucinous colorectal cancer
Authors: Jee-Woo Seo, Jae-Yoon Kim, Ye-Jin Ha, Seung-Woo Baek, Jong-Lyul Park, Sun-Woo Lee, Jong-Lyul Lee, Seon-Young Kim, Seon-Kyu Kim
Journal: Cancer Research (2025)

Abstract Backgrounds: Mucinous adenocarcinoma (MuC), a unique subtype of colorectal cancer (CRC), exhibits distinct molecular features and is associated with poorer outcomes compared to non-mucinous adenocarcinoma (NMuC). Standard CRC treatments often overlook the molecular diversity within CRC, especially in stage II, where the benefit of adjuvant chemotherapy remains debated. Biomarkers are needed to improve risk assessment and guide tailored treatments. Methods: We conducted molecular profiling of 259 CRC samples, including MuC and NMuC subtypes, to identify MuC-specific gene signatures. A 23-gene risk score (MuC-RS) was developed and validated in four independent cohorts (n = 1, 157). Prognostic significance of MuC-RS was assessed using various statistical methods, including Kaplan-Meier survival analysis, log-rank tests, and Cox regression. Results: In the discovery cohort of fresh-frozen tissues, unsupervised clustering revealed distinct gene expression patterns differentiating MuC from NMuC. MuC showed notable enrichment in fibroblast-associated genes, EMT pathways, and mucin glycosylation processes. The MuC-RS effectively stratified patients into high-risk (MuC-H) and low-risk (MuC-L) categories. Multivariate analysis confirmed MuC-RS as an independent prognostic factor. Importantly, stage II MuC-L patients showed limited response to standard chemotherapy but increased responsiveness to immune checkpoint inhibitors (ICIs), associated with higher tumor mutation burden and immune activation. MuC-RS's prognostic utility was further validated through comparisons with consensus molecular subtypes. Conclusion: MuC-RS offers a promising tool for predicting recurrence and informing personalized treatment strategies in CRC, potentially enhancing risk stratification and supporting novel therapies, such as ICI, particularly for stage II MuC patients. Grant Support: This research was supported by the Bio &amp; Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2022R1A2C2008480 to S.K. Kim, 2018R1C1B6008571 and 2022R1F1A1074317 to J.L. Lee). This study was also supported by grants from the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM5192423). Citation Format: Jee-Woo Seo, Jae-Yoon Kim, Ye-Jin Ha, Seung-Woo Baek, Jong-Lyul Park, Sun-Woo Lee, Jong-Lyul Lee, Seon-Young Kim, Seon-Kyu Kim. Construction of a 23-gene risk scoring system to predict disease recurrence and chemotherapy response in mucinous 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 3356.
Abstract 242: Differential activation of TAM receptors by Gas6 and protein S
Authors: Ziren Wang, Samhita Bapat, Varsha Gadiyar, Christopher Varsanyi, Rachael Pulica, Trevor Frederick, Ahmed Aquib, Raymond Birge
Journal: Cancer Research (2025)

Abstract Tyro-3, Axl, and Mertk (abbreviated TAM receptors) comprise a homologous family of type I receptor tyrosine kinases (RTKs) have been shown to have increasingly important roles for both homeostasis, particularly for anti-inflammation and the resolution of inflammation. While previous studies have shown that TAM receptors are differentially expressed on immune cells, surprisingly much less is currently known about the differential functional activities and expression of the major TAM ligands, Growth Arrest Factor-specific gene 6 (Gas6) and Protein S (Pros1), particularly whether they have overlapping or distinct biochemical and cellular functions, and how they regulate the interplay between inflammation and coagulation. To evaluate the functions of Gas6 and Pros1, we first cloned and expressed human proteins for testing on TAM-IFNgR1 reporter cell lines. While both Gas6 and Pros1 require post-translational gamma-carboxylation of their Gla domains for biological activity and binding to phosphatidylserine (PS), they possess differential capacity to bind soluble Axl and C4BP. Moreover, both Gas6 and Pros1 require the 4 tandem EGF-like domains for their activity, and both appear to require extracellular protein disulfide isomerase activity for receptor activation. Taken together, we have identified a novel mechanism for TAM activation by Gas6 and Pros1, as well as both overlapping and non-overlapping activities with respect to ligand-dependent receptor activation. These results have potential implications in both cancer and inflammation. Citation Format: Ziren Wang, Samhita Bapat, Varsha Gadiyar, Christopher Varsanyi, Rachael Pulica, Trevor Frederick, Ahmed Aquib, Raymond Birge. Differential activation of TAM receptors by Gas6 and protein S [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 242.
Abstract 4007: Building 3D ex vivo models as a powerful platform for anti-cancer drug and biomarker discovery
Authors: Fu-Ju Chou, Annamaria Rapisarda, Mara Gilardi, Stefano Cairo, BanuPriya Sridharan
Journal: Cancer Research (2025)

Abstract Patient-derived models have increasingly been adopted into target validation, lead-optimization and secondary screening campaigns to move translation ahead in drug discovery. While 2-dimentional cell line in vitro models continue to play a pivotal role in early screening studies, new advanced in 3D patient derived organoids (PDO) and patient derived xenograft organoids (PDX-O) technology have made it suitable to meet the rigor and reproducibility of traditional screening metrics. At Champions Oncology, we have built a successful pipeline of ex vivo models from pre-treated, metastatic, and genetically diverse cohorts across varied indications. PDX-derived cell cultures serve as (i) physiologically relevant high throughput platforms for early or clinical hypothesis testing, (ii) cellular systems to gain mechanistic and phenotypic insights into drug mode of action in 3D tumor microenvironment, and (iii) cost-effective translational bridge to well-informed in vivo studies. Ex vivo models have been widely established and characterized for non-small cell lung cancer (NSCLC), colorectal (CRC), and other epithelial tumor types. Indications such as renal cell carcinoma (RCC), Diffuse large B-cell lymphoma (DLBCL), gastric and bladder cancer, glioblastoma multiforme (GBM), prostate cancer, and sarcoma are less common and often a size-able cohort size rarely exists. In this poster, we showcase our recent efforts on the iterative media optimization process, growth kinetics, and morphology of models from these rare indications and characterization data that establish them front and center as valid preclinical screening tools. Through careful media formulation, the appropriate standard of care controls (SoC), and vigorous assay development criteria we show the versatility of these models for both efficacy and complex mechanistic readouts when probed with various modalities including antibody-drug conjugates (ADC) and anti-sense oligos (ASO). Our experience establishing 3D microstructures from various indications by iterative optimization of culture conditions is further validated by our comprehensive quality control (QC) procedures and deep molecular and pharmacological characterization. In summary, through a series of examples, we highlight the application of Champions TumorGraft3D Ex vivo models in enhancing the biological and clinical fidelity of novel modalities of drugs and/or novel drug combinations. Citation Format: Fu-Ju Chou, Annamaria Rapisarda, Mara Gilardi, Stefano Cairo, BanuPriya Sridharan. Building 3D ex vivo models as a powerful platform for anti-cancer drug and biomarker discovery [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 4007.