tbuckley/cabot-search huggingface dataset:
Abstract 518: Repurposing of pralatrexate in gastric cancer: Inducing cell death via SMO inhibition and GLI1 suppression
Authors: Hyemi Yun, Bo Ram Kim, Bu Gyeom Kim, Dae Yeong Kim, Okhyeon Kim, Yoon Namgung, Jun Woo Bong, Sanghee Kang, Sun Il Lee, Sang Cheul Oh
Journal: Cancer Research (2025)

Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide. Currently, GC has serious drug resistance and side effects to existing treatments, and the development of new treatments is urgently needed. Abnormal activation of Hedgehog (Hh) signaling can promote the proliferation, metastasis, and drug resistance of GC cells and inhibit apoptosis. In gastrointestinal cancer, the expression of components of the Hh signaling pathway and their target genes are upregulated. Through TCGA analysis, we found that among the five types of digestive cancers: cholangial, colorectal, gastric, hepatocellular, and pancreatic, GC is most affected by Hh signaling. Pralatrexate is an FDA-approved drug originally used to treat relapsed or refractory peripheral T-cell lymphoma (PTCL). Research has been conducted on its anticancer efficacy in solid carcinomas such as Non-small cell lung cancer (NSCLC), but its efficacy in GC remains unexplored. In a previous study, screening results using an FDA-approved drug library showed that Pralatrexate inhibits GLI-dependent luciferase activity. In this study, we demonstrated that Pralatrexate canonically regulates Hh signaling by downregulating SMO. Structural predictions using AI modeling indicated that Pralatrexate binds to a site similar to the SMO antagonist ANTA-XV, distinct from Cyclopamine's binding pocket. It was confirmed that Pralatrexate causes degradation of SMO, and GLI1 was subsequently degraded by lysosome. This suppression of Hedgehog (Hh) signaling results in reduced cell proliferation and the induction of apoptosis. In summary, Pralatrexate canonically regulates Hh signaling by inhibiting SMO and suppressing GLI1, ultimately reducing cell proliferation and causing apoptosis in GC. Our findings uncover a novel anticancer mechanism of Pralatrexate in GC, providing a potential basis for its clinical application in GC therapy. Citation Format: Hyemi Yun, Bo Ram Kim, Bu Gyeom Kim, Dae Yeong Kim, Okhyeon Kim, Yoon Namgung, Jun Woo Bong, Sanghee Kang, Sun Il Lee, Sang Cheul Oh. Repurposing of pralatrexate in gastric cancer: Inducing cell death via SMO inhibition and GLI1 suppression [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 518.
Abstract 3073: Metabolic dependency on de novo pyrimidine synthesis in platinum resistant ovarian cancer
Authors: Horacio Cardenas, Guangyuan Zhao, Ana Maria Isac, Daniela E. Matei
Journal: Cancer Research (2025)

Abstract Background: High grade serous ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Materials and Methods: We used cisplatin resistant (Cis-R) cells generated by repeated cisplatin treatment of sensitive (Cis-S) OC cell lines, transcriptomic and metabolomic analyses to identify key metabolic pathways associated with platinum resistance. In vivo experiments used intraperitoneal (ip) OC xenografts and patient derived xenografts (PDX). Results: Pathway analysis of differentially abundant metabolites in Cis-R vs. Cis-S OVCAR5 and COV362 cells identified enrichment of pyrimidine metabolism (FDR&amp;lt;0.05) related to increased de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in Cis-R cells. Inhibition of this pathway using the DHODH inhibitor brequinar (BRQ) decreased cell viability and induced expression changes in genes of the mitochondrial electron transport in Cis-R compared with Cis-S cells. Oxygen consumption rate (OCR) measured with a Seahorse assay indicated lower (P&amp;lt;0.05) OCR (baseline, ATP-related, and maximal) and spare respiratory capacity (SRC) in Cis-R vs. Cis-S OVCAR5 cells. BRQ induced dose-related inhibition of OCR in both Cis-R and Cis-S cells. SRC was inhibited by BRQ only in Cis-R cells. In vivo, BRQ attenuated growth of ip Cis-R OC xenografts but did not alter Cis-S tumors. Tumor growth was also inhibited (p&amp;lt;0.01) by BRQ in a Cis-R PDX model. BRQ plus carboplatin enhanced (p&amp;lt;0.05) the inhibitory effects of carboplatin alone in ip Cis-R OC xenografts. Conclusions: Our results support that Cis-R cells acquire dependency on the de novo pyrimidine synthesis and maintain relatively low levels of mitochondrial oxidation, rendering Cis-R cells and tumors vulnerable to inhibitors of this pathway. Citation Format: Horacio Cardenas, Guangyuan Zhao, Ana Maria Isac, Daniela E. Matei. Metabolic dependency on de novo pyrimidine synthesis in platinum resistant ovarian 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 3073.
Abstract 724: Target identification for antibody-drug-conjugate (ADC) therapy in biliary tract cancers (BTC)
Authors: Aruj Dhyani, Zeynep Tarcan, Joanne Chou, Rohit Thummalapalli, Walid Chatila, Sharanya Nag, Ezra Rosen, Sydney Bowker, Wungki Park, Elisa De Stanchina, Sarat Chandarlapaty, David Solit, William Jarnagin, Marinela Capanu, Eileen M O'Reilly, Ghassan K Abou-Alfa, Olca Basturk, James Harding
Journal: Cancer Research (2025)

Background: BTCs are an uncommon malignancy with poor prognosis. ADCs have efficacy in several solid tumors with antigen surface expression serving as a potential biomarker in some instances. Herein, we evaluate the protein expression and heterogeneity of ADC target antigens and their prognostic implications in BTC. Methods: Utilizing an IRB-approved, retrospective biospecimen protocol, we constructed tissue microarrays (TMA) from resected, early staged intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GB). IHC for Nectin-4, TROP2, c-MET, CLDN18.2 was assessed. Positivity defined as ≥10% weakly stained tumor cells and quantified by H-score (intensity × percentage). HER2 IHC scored per standard colon criteria. Clinicopathological factors and outcomes were associated with ADC target expression. Results: N=65 resected cases were selected (median age 72 years (range 36-92); 55% males, anatomical subtype 40% IHC, 43% EHC, 17% GB; 84% moderately differentiated adenocarcinoma. c-MET and TROP2 were expressed in 75% and 83% of cases with differential expression based on anatomic site (c-MET: IHC: 62%, EHC: 89% vs GB: 73%, p=0.049; TROP2: IHC: 65%, EHC: 93% vs GB: 100%, p=0.010, Table). HER2, CLDN18.2, and Nectin-4 were expressed in 7.7%, 46%, and 66% of cases, and did not differ based on anatomic site. Median RFS and OS were 20 (95%CI 10-NR) and 40 (95%CI 27-NR) months respectively and outcomes were not impacted by expression of HER2, Nectin-4, TROP2, c-MET, or CLDN18.2. Conclusion: Modest to high expression of Nectin-4, TROP2, c-MET and CLDN18.2 was identified across BTC anatomic subtypes, suggesting a potential role for ADCs to these antigens in patients with BTC. Preclinical validation is ongoing in BTC patient derived xenografts with trastuzumab deruxtecan (HER2 sensitive and HER2 resistant models), enfortumab vendotin (Nectin-4 positive model), and sacituzumab govitecan and these results will be presented at the meeting. Citation Format: Aruj Dhyani, Zeynep Tarcan, Joanne Chou, Rohit Thummalapalli, Walid Chatila, Sharanya Nag, Ezra Rosen, Sydney Bowker, Wungki Park, Elisa De Stanchina, Sarat Chandarlapaty, David Solit, William Jarnagin, Marinela Capanu, Eileen M O'Reilly, Ghassan K Abou-Alfa, Olca Basturk, James Harding. Target identification for antibody-drug-conjugate (ADC) therapy in biliary tract cancers (BTC) [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 724.
Abstract 42: Non-small cell lung cancer (NSCLC) patient derived xenograft organoids (PDX-O) as a model for testing novel therapeutic approaches
Authors: Maia G. Clare, Robert B. Cameron, Nia G. Hammond, Massar Alsamraae, Brandon Faubert
Journal: Cancer Research (2025)

Abstract Despite advances in therapy and early screening, non-small cell lung cancer (NSCLC) remains responsible for the most cancer-related deaths worldwide. There is an urgent need to elucidate the drivers of NSCLC progression to develop better treatment options, but these efforts are often limited by a lack of clinically relevant model systems. To address this need, we developed a series of patient-derived xenografts (PDX) from a clinical study of tumor metabolism. We confirmed that these models retain the genetic, metabolic, and metastatic phenotypes of the patient tumor. Furthermore, we developed patient-derived organoids (PDOs) from these systems by growing and passaging PDX cells in Matrigel droplets with the ThermoFisher OncoPro System. Preliminary validation studies have revealed these organoids have expected morphology, high viability, and maintenance of NSCLC expression markers. We have used these novel model systems to identify heterogeneous metabolic phenotypes and identify targetable vulnerabilities. Specifically, we have used a drug screening approach to combine metabolic inhibitors with standard of care chemotherapies to evaluate combinatorial treatment strategies in NSCLC by cancer cell death. In summary, we have developed a bedside-to-bench approach of identifying patient-relevant tumor biology, in tractable, testable systems, and we use these models to identify novel therapeutic approaches in NSCLC. Citation Format: Maia G. Clare, Robert B. Cameron, Nia G. Hammond, Massar Alsamraae, Brandon Faubert. Non-small cell lung cancer (NSCLC) patient derived xenograft organoids (PDX-O) as a model for testing novel therapeutic approaches [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 42.
Abstract 994: Advancing health equity and reducing disparities in prostate cancer in Black men: iCCaRE
Authors: Kimlin Tam Ashing, Timethia Bonner, Ewan K. Cobran, Folakemi Odedina, Aj Merriweather, Ernie Kaninjing, Floyd Willis, Cassandra Moore, Joanne Oliver, Fornati Bedell, John McCall
Journal: Cancer Research (2025)

Abstract In the US and globally, Black men experience the highest prostate cancer burden among all racial and ethnic groups, underscoring the urgent need for research to guide the development and implementation of culturally tailored strategies aimed at reducing disparities and improving outcomes. In response, the Inclusive Cancer Care Research Equity (iCCaRE) Consortium was created to advance health equity and reduce disparities in prostate cancer. Importantly, a Survivorship Care Plan (SCP) is recommended to educate and empower patients, enabling them to be better informed about their cancer diagnosis, treatment, and survivorship care recommendations. To date, there is no SCP targeted to Black prostate cancer survivors (CaPS) who have the greatest disparities with the poorest survivorship outcomes (ACS F&amp;F; AACR HD Report; Fullwood, 2024). Therefore, we aimed to develop a SCP tailored for Black men. Addressing the unique needs of Black men require a genuine bidirectional relationship between scientist and the community rooted in community engaged research (CER). The SCP was first informed by the literature (Bonner, 2024) and the ASCO template (canceradvocacy.org). With input from the iCCaRE leadership and the Partnership Engagement Services (PES) Core, the Whole Person SCP better responds to the informational, clinical and quality of life needs of Black Prostate Cancer survivors. Based on CER, we included 22 diverse, Black CaPs to further guide and tailor the iCCaRE. Our findings indicate that the iCCaRE Survivorship Care Plan (SCP) enhanced the ASCO template by incorporating and expanding several unique domains, including family history, care team contacts, follow-up and surveillance, symptoms, quality of life, survivor concerns, major comorbidities, health advisories, and culturally relevant resources, creating a comprehensive, whole-person SCP tailored specifically for Black men. It is crucial to continue to improve support for clinical research and advocate for Black men and their communities to reduce prostate cancer burden. Prostate cancer also needs to include incidence, mortality, and disparities for Black men to raise awareness of scarcely studied field of Black men and prostate cancer survivorship. Citation Format: Kimlin Tam Ashing, Timethia Bonner, Ewan K. Cobran, Folakemi Odedina, Aj Merriweather, Ernie Kaninjing, Floyd Willis, Cassandra Moore, Joanne Oliver, Fornati Bedell, John McCall. Advancing health equity and reducing disparities in prostate cancer in Black men: iCCaRE [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 994.
Abstract 2633: Mechanisms of SEMA4D mediated blood brain barrier transmigration
Authors: Anu D. Sunkara, Remi Klotz, Min Yu
Journal: Cancer Research (2025)

Abstract Brain metastasis poses a challenge in cancer treatment due to its prevalence, diagnostic complexities, and the limited efficacy of systemic therapies due to the blood brain barrier (BBB). Previous work in our lab utilized patient-derived Circulating Tumor Cell (CTC) lines established from the peripheral blood of patients with metastatic luminal breast cancers to investigate the molecular features that allow a subset of CTCs to adapt and grow in the brain. This study identified Semaphorin 4D (SEMA4D), a transmembrane receptor that facilitates BBB transmigration, both in vitro and in vivo, through its interaction with the Plexin B1 (PLXNB1) receptor. Together with oncogene MYC, SEMA4D facilitates the colonization of the brain and promotes brain metastasis of CTCs. In this study, we propose investigating the hypothesis that the reverse signaling via the cytoplasmic region of SEMA4D activates the Yes Associated Protein (YAP) pathway, facilitating BBB transmigration. Our data shows that truncating the cytoplasmic region of SEMA4D (deleting the PDZ binding domain) in the BT474 HER2 positive cell line reduces BBB transmigration. In addition, cells that are overexpressed with SEMA4D showed nuclear localization of YAP via immunofluorescence. Hence, using patient-derived CTC cultures and a model system of breast cancer cell lines we aim to elucidate SEMA4D’s link to YAP signaling and the mechanism of BBB transmigration. Understanding the mechanisms underlying metastatic invasion through the BBB is crucial for developing targeted interventions in the future. Citation Format: Anu D. Sunkara, Remi Klotz, Min Yu. Mechanisms of SEMA4D mediated blood brain barrier transmigration [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 2633.
Abstract 1475: HDAC8 as a critical regulator of cancer cell genome stability: therapeutic implications
Authors: Zih-Yao Yu, Wei-Jan Huang, Stanton Gerson, Sung-Bau Lee
Journal: Cancer Research (2025)

Abstract In cancer cells, chromatin replication is often misregulated in part due to mutations in oncogenes and tumor suppressor genes, leading to increased replication stress and genomic instability. While this instability drives cancer progression, it also makes cancer cells more dependent on genome maintenance pathways, presenting a therapeutic target. A promising strategy is to exacerbate replication stress, causing lethal genome instability. We have developed a sensitive reporter to monitor replication stress via single-stranded DNA at stressed forks. Our earlier study identified Tousled-like kinases (TLKs) crucial for chromatin assembly during genome replication and discovered TLK inhibitors to treat cancers through increasing replication stress. Additionally, we recently uncovered histone deacetylase 8 (HDAC8) inhibitors that disrupt chromatin replication and compromise genome integrity, particularly when combined with checkpoint kinase inhibitors. In this presentation, I will show you how HDAC8 behaves as caretakers of genetic and epigenetic integrity and how we targeted replication stress to create cancer-specific synergistic vulnerabilities. Citation Format: Zih-Yao Yu, Wei-Jan Huang, Stanton Gerson, Sung-Bau Lee. HDAC8 as a critical regulator of cancer cell genome stability: therapeutic implications [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 1475.
Abstract 2462: Novel digital pathology algorithms to explore the role of tumor microenvironment in next generation immuno-oncology clinical trials utilizing 17 plex fluorescent immunohistochemistry
Authors: Richard Van Krieken, Jaspreet Kaur, James Santos, Naveen Dakappagari, Jennifer Bordeaux
Journal: Cancer Research (2025)

Abstract Purpose: A deeper understanding of the intricacies between tumor microenvironments (TMEs) and immune cell infiltrates is critical for creation of next generation immune modulating therapies. We previously validated a clinical grade, 17 plex tumor immune landscape assay which characterizes T cells, B cells, myeloid cells, plasma cells, and tumor cells across five major cancer types. This assay was developed on the Orion platform, which images up to 18 markers concurrently and allows for same slide hematoxylin and eosin (H and E). Using the Orion platform, we characterized the TME through two approaches: cellular neighborhoods and clustering based on H and E and segmented fluorescent immunohistochemistry data. Our findings elucidate innovative strategies for leveraging high dimensional data from Orion to uncover clinically useful insights, opening new avenues for understanding mechanism of response or resistance in next generation immune oncology (IO) clinical trials Study Design: We designed a mFIHC assay (Granzyme B, Ki67, CD3e, CD20, CD4, CD163, CD8a, CD56, PDL1, PD1, LAG3, FOXP3, CD11b, CD138, SOX10, Cytokeratin and Hoechst) to evaluate expression of immune markers on non small cell lung cancer, breast carcinoma, colorectal cancer, prostate cancer and melanoma. After the initial evaluation, we validated the mFIHC assay for clinical trial use with automated staining (IntelliPath FLX) and imaging (Orion). Image analysis was conducted using HALO technologies. Results: HALO analysis revealed distinct tumor immune microenvironments in the examined tissues. Microenvironment data were assessed by analyzing immune cell infiltration alongside immune activation markers. Our analysis revealed unique cell clusters in these microenvironments. Conclusion: Our clinically validated 17 plex mFIHC assay, combined with advanced spatial algorithms, offers improved characterization of the TME. We expect these novel algorithms to contribute to gaining novel insights into tumor biology and development of next generation IO therapies. Citation Format: Richard Van Krieken, Jaspreet Kaur, James Santos, Naveen Dakappagari, Jennifer Bordeaux. Novel digital pathology algorithms to explore the role of tumor microenvironment in next generation immuno-oncology clinical trials utilizing 17 plex fluorescent immunohistochemistry [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 2462.
Abstract 2496: GOALS: a novel approach for gene ontology analysis using layered shell to enhance functional insight mining in cancer genomics
Authors: Zongliang Yue, Christopher D. Willey, Robert S. Welner, Rajesh Amin, Jake Y. Chen
Journal: Cancer Research (2025)

Abstract Gene Ontologies (GOs) are standardized descriptions of gene functions in terms of biological processes, molecular functions, and cellular components, capturing their Parent-Child relationships in a structured framework and advancing cancer biological modeling to provide consistent and meaningful insights into functional genomics analysis. The conventional GO hierarchical structure is defined by human curation experts, with levels determined by the shortest path to the root term. However, grouping GOs poses challenges due to the uneven distribution of gene members within GO terms and inconsistencies in the level of detail across terms at the same GO level. In this work, we introduce Gene Ontology Analysis using Layered Shells (GOALS), a novel tool that discretizes GOAs into optimal layers. GOALS creates a scalable number of GO layers (typically within 10) while maintaining a balanced number of genes across GOs in each layer. Unlike existing tools, GOALS organizes GO terms using a bottom-up approach based on their co-membership network, discreting GOs to achieve an exponential fit with GO’s gene member size. Meanwhile, GOALS reveals clusters or supersets reflecting biological relevance by unsupervised clustering of GO’s latent projections. In the glioblastoma (GBM) and chronic myeloid leukemia (CML) case studies, GOALS identified distinct GO functional clusters with multi-GO layers to reveal multiple levels of detail—from specific to abstract contexts—to maximize signal discovery and uncover those signal’s association with drug resistance. More importantly, GOALS outperformed existing enrichment analysis tools by effectively classifying functional differences with varying treatment outcomes. GOALS offers a robust and innovative framework for exploring disordered GO clusters, mining GO activities, and analyzing potential GO-GO interplays. By addressing critical challenges in functional genomics, GOALS provides a powerful tool for advancing our understanding of cancer heterogeneity and uncovering actionable insights for therapeutic development. Citation Format: Zongliang Yue, Christopher D. Willey, Robert S. Welner, Rajesh Amin, Jake Y. Chen. GOALS: a novel approach for gene ontology analysis using layered shell to enhance functional insight mining in cancer genomics [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 2496.