tbuckley/cabot-search huggingface dataset:
Abstract 3550: Dendritic cells pulsed with cancer stem cell antigen showed profound anti-tumoral efficacy in ovarian cancer
Authors: Haixi Liang, Tong Xiang, Lin Zhou, Zhiwen Xie, Mao Ye, Chunyan Lan
Journal: Cancer Research (2025)

Abstract Background: Ovarian cancer serves as the first leading lethally gynecologic cancer, of which around 70% of patients would relapse soon even have undergone standard treatment. Several mechanisms work together attributing to the early relapse. Among these, cancer stem cells (CSCs) act as the root of metastasis and relapse in the early reports. However, limited methods directly targeting these rare populations have been developed so far. Here we develop DC vaccine directly targeting CSCs by loading DCs with enriched cancer stem cell antigen (CSC-Ag) in vitro. Methods: Freshly dissected ovarian tumors are digested into single cell suspension with digestive enzymes. Subsequently, fluorescence-activated cell sorting (FACS) is used to isolate CD44CD133 double-positive cells, previously reported surface markers of CSCs. Basic medium supplied with several cytokines is used to maintain and enrich CSCs. Suspension of enriched stem cell spheres is repeated five freeze-thaw cycles in liquid nitrogen and 37-degree Celsius water bath, and the supernatant after centrifugation is regarded as CSC-Ag. CD14+ cells of patients’ PBMCs are isolated using CD14 microbeads according to manufacturer’s instruction. IL-4 and GM-CSF are added to induce DC. Immature DC are loaded with previously prepared CSC-Ag. Meanwhile, CD14- cells are cultured with the supplement of anti-CD3, anti-CD28 antibodies, and rhIL-2. T cells are soon co-cultured with mature DC for further antigen-presenting. In vitro cytotoxicity against OC cell lines are tested. Additionally, we developed a peritoneal metastatic ovarian cancer cell model by injecting OVCAR8 transfected with luciferase into NSG mice. IVIS system is used later to monitor tumor growth twice a week. Result: Both CD44 and CD133 were highly expressed in ovarian cancers compared with normal tissue in matched TCGA and GTEx datasets. CD44CD133 double-positive cells ranged from 0.00% to 59.10% in our OC cohort (n=21). CSCs were successfully isolated and enriched, confirmed by the expression of stem cell markers, including SOX2, OCT4, and NANOG. CSC-Ag also expressed those markers comparable to freshly cultured CSC. DC-CSC+T showed remarkable efficacy both in vitro and in vivo against ovarian cancer, with more cancer cell apoptosis. Conclusion: Dendritic cells pulsed with cancer-stem cell antigen (DC-CSC+T) could significantly lower the growth rate of OC, and may serve as a potential adjuvant therapy for improving OC disease-free interval. Citation Format: Haixi Liang, Tong Xiang, Lin Zhou, Zhiwen Xie, Mao Ye, Chunyan Lan. Dendritic cells pulsed with cancer stem cell antigen showed profound anti-tumoral efficacy in 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 3550.
Abstract 4722: Crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors
Authors: Yan Wang, Linyan Tian, Chengming Liu, Sufei Zheng, Huiyang Shi, Fang Wei, Wenxin Jiang, Yucheng Dong, Haiyan Xu, Enzhi Yin, Nan Sun, Jie He
Journal: Cancer Research (2025)

Abstract Objective: KRAS-G12C inhibitors are promising in targeted therapeutic strategies. However, it remains uncertain to search for biological reminders of clinical outcomes and early resistance. Methods: Systematic review has been performed up to September, 2024 to evaluate treatment efficacy and beneficial patients. We constructed KEAP1 and STK11 knockout mutants with CRISPR/Cas9 technology and PD-L1 overexpression mutants with lentiviral vectors. The sensitivity of cells to different KRAS-G12C inhibitors was assessed using CCK-8 assays. Potential pathways of resistance were identified through comprehensive bioinformatics analyses. Results: 13 clinical trials with 1, 132 enrolled patients indicated remarkable clinical efficacy and benefit the senior and the female. Patients with liver and brain metastases also tends to benefit from KRAS-G12C inhibitors. KEAP1 mutation serves as a critical negative biomarker for early progression and resistance. Validation studies indicated a notable increase in IC50 values for different KRAS-G12C inhibitors after KEAP1 knockout (P &amp;lt; 0.0001). Differentially expressed genes in KEAP1 knockout cells versus contrast groups were conducted with GO, KEGG, and Reactome pathway analyses, suggested evident enrichment in extracellular matrix organization and cell adhesion processes. In addition, STK11 mutations and an increasing PD-L1 expression level reminds of worse prognosis, despite absence of significant difference. Conclusion: This research considered KRAS-G12C inhibitors as optional therapy and selected some subgroups who are more likely gain benefits from targeted therapy. As a key adverse biomarker, KEAP1 mutation tends to affect extracellular matrix organization and cell adhesion and promotes early resistance. Citation Format: Yan Wang, Linyan Tian, Chengming Liu, Sufei Zheng, Huiyang Shi, Fang Wei, Wenxin Jiang, Yucheng Dong, Haiyan Xu, Enzhi Yin, Nan Sun, Jie He. Crucial prognostic biomarkers for resistance to KRAS-G12C 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 4722.
Abstract 3545: Enhancing anticancer immunity with SARS-CoV-2 B cell epitope-guided neoantigen nanovaccines
Authors: Chengyi Li, Fang Ke, Shuai Mao, Zera Montemayor, Mohamed Dit Mady Traore, Alejandra Duran Balsa, Mahamadou Djibo, Neha Karekar, Hanning Wen, Wei Gao, Duxin Sun
Journal: Cancer Research (2025)

Abstract Background: Current neoantigen cancer vaccines primarily rely on dendritic cell- and macrophage-mediated antigen presentation to activate T cell immunity. However, the potential of incorporating B cell-mediated antigen presentation into these vaccines to enhance CD4 and CD8 T cell responses has not been fully explored. Methods: We developed BSARSTNeoAgVax, a SARS-CoV-2 B cell epitope-guided neoantigen peptide or mRNA cancer nanovaccine, designed to leverage B cell-mediated antigen presentation. BSARSTNeoAgVax was tested in three mouse cancer models (melanoma, pancreatic cancer, and breast cancer) using two types of T cell tumor neoantigens (peptide or mRNA) and two types of nano delivery systems (I or lipid nanoparticles, LNP). SARS-CoV-2 B cell epitopes were conjugated on the surface of I or LNP to facilitate crosslinking with the B cell receptor (BCR) on SARS-CoV-2-specific B. Immune responses and therapeutic efficacy of BSARSTNeoAgVax were compared with existing neoantigen vaccines. Results: BSARSTNeoAgVax enabled SARS-CoV-2 B cell-mediated antigen presentation to tumor-specific CD4 T cells, significantly enhancing the activation of tumor-specific follicular and non-follicular CD4 T cells. This interaction also promoted B cell-dependent tumor-specific CD8 T cell immunity, resulting in robust antitumor responses. Importantly, the efficacy of BSARSTNeoAgVax was independent of antibody production, as the SARS-CoV-2 B cell epitopes on the vaccine generated anti-SARS-CoV-2 antibodies that lacked anticancer efficacy. In the mouse cancer models, BSARSTNeoAgVax demonstrated superior efficacy, showing improved tumor control and enhanced immune activation compared to current neoantigen vaccines. Conclusion: Our findings establish a universal platform for cancer immunotherapy, utilizing SARS-CoV-2 B epitope-guided neoantigen nanovaccines to enhance CD4 and CD8 T cell antitumor immunity through viral-specific B cell-mediated antigen presentation. This approach holds significant promise for improving the efficacy of neoantigen-based cancer vaccines across diverse tumor types. Citation Format: Chengyi Li, Fang Ke, Shuai Mao, Zera Montemayor, Mohamed Dit Mady Traore, Alejandra Duran Balsa, Mahamadou Djibo, Neha Karekar, Hanning Wen, Wei Gao, Duxin Sun. Enhancing anticancer immunity with SARS-CoV-2 B cell epitope-guided neoantigen nanovaccines [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 3545.
Abstract 4280: DWP216, a novel TEAD1 selective inhibitor for NF2 mutant tumors and drug-tolerant persister cells
Authors: Bora Yoo, YoungKu Kang, Won An, Seul Lee, Inyoung Lee, Ahreum Kwon, Eunji Ha, Hyoungrok Bak, Ji-Duck Kim, Joon Seok Park
Journal: Cancer Research (2025)

Abstract Neurofibromatosis type 2 (NF2) controls the Hippo pathway signaling through YAP and TEAD axis. NF2 mutation leads to YAP and TEAD activation and is reported in malignant mesothelioma with 30-40% and meningioma with 50%. Furthermore, drug-tolerant persister cells to EGFR inhibitor or KRAS inhibitor show up-regulation of YAP and TEAD. Four isoforms of TEAD (1-4) are highly conserved and each TEAD isoform has the different biological function depending on organ and co-factors. DWP216, a TEAD1 selective inhibitor, shows the excellent in vitro activities. DWP216 also inhibits TEAD1 activity, TEAD1 palmitoylation and interaction between TEAD1 and YAP1 by binding to palmitate binding pocket of TEAD1. Pharmacokinetic parameter of DWP216 present good druglike properties with blood-brain barrier penetration. DWP216 has the superior in vivo efficacy compared to TEAD1 selective inhibitor and pan-TEAD inhibitor. Moreover, we found that TEAD1 is a key regulator for drug-tolerant persister cells to targeted therapy. Combination of DWP216 and EGFR inhibitor or KRAS inhibitor show synergistic anti-cancer effect in vitro and in vivo. In conclusion, DWP216 is a promising TEAD1 selective inhibitor for NF2 mutant tumor and may be a proper option for drug-resistance of targeted therapy. DWP216 is preparing toward to IND filing for Phase 1 in 2025. Citation Format: Bora Yoo, YoungKu Kang, Won An, Seul Lee, Inyoung Lee, Ahreum Kwon, Eunji Ha, Hyoungrok Bak, Ji-Duck Kim, Joon Seok Park. DWP216, a novel TEAD1 selective inhibitor for NF2 mutant tumors and drug-tolerant persister 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 4280.
Abstract 3036: Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic anti-cancer effects in AR-V7-expressing mCRPC preclinical models
Authors: Benjamin C. Brim, Andres F. Leon, Erica L. Beatson, Jessica D. Kindrick, Kinjal Bhadresha, Xiaohu Zhang, Giulia C. Napoli, Emily N. Risdon, Keith T. Schmidt, Erin Beck, Carleen Klumpp-Thomas, Michele Cerebelli, Douglas K. Price, Cindy H. Chau, Craig J. Thomas, William D. Figg
Journal: Cancer Research (2025)

Abstract There is an unmet need to develop novel treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). Patients often develop resistance to hormonal therapies that target the AR-axis (e.g., abiraterone, enzalutamide). A splice variant of AR, AR-V7, is associated with resistance to these inhibitors as well as mCRPC progression and poor prognoses. We embarked upon a high-throughput screen to identify synergistic combinations of targeted therapies using two CRPC cell lines, LNCaP95 and VCaP-CR. The goal of the drug screen is to identify rational targeted combination therapies for mCRPC, where efficacy can be achieved at lower, equally effective doses in order to minimize toxicity. Extensive bioinformatic analysis identified several synergistic combinations, including dual targeting of Bcl-2 family proteins using BH3 mimetics. Combinations targeting Bcl-xL (A-1331852 and Navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) as early as two hours post-treatment. The effect of the treatment combination on downstream targets was assessed via western blot analysis. We demonstrated synergistic anti-tumor effects with Mcl-1/Bcl-xL co-targeting in three-dimensional (3D) spheroid CRPC models and in the patient-derived LuCaP-167CR organoid model, which represents a more physiologically relevant model for evaluating drug response and efficacy. We also explored the use of a Bcl-xL-specific PROTAC to minimize platelet toxicity associated with Bcl-xL inhibitors in the clinic. We showed similar synergistic efficacy with the S63845/Bcl-xL targeting PROTAC combination in the 3D spheroid models compared to the small-molecule Bcl-xL inhibitors while also inducing apoptosis. Our findings provide unique insight into the dependence on Bcl-2 family proteins in mCRPC. Our findings also support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC. Citation Format: Benjamin C. Brim Andres F. Leon Erica L. Beatson Jessica D. Kindrick Kinjal Bhadresha Xiaohu Zhang Giulia C. Napoli Emily N. Risdon Keith T. Schmidt Erin Beck Carleen Klumpp-Thomas Michele Cerebelli Douglas K. Price Cindy H. Chau Craig J. Thomas William D. Figg. Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic anti-cancer effects in AR-V7-expressing mCRPC preclinical 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 3036.
Abstract 5754: An LC-MS toolbox for identifying and guiding the development of cysteine-targeted small molecule covalent inhibitors
Authors: Kurt Baltier, Alison Erickson, Craig R. Braun, Ryan Kunz, Brian Erickson
Journal: Cancer Research (2025)

Covalent inhibitors are a powerful class of therapeutic agents, and have gained particular traction with oncogenic targets. FDA-approved covalent inhibitors have been introduced for treatment of a range of cancers, including mantle cell lymphoma (ibrutinib), non-small cell lung cancer (osimertinib, sotorasib, afatinib), and breast cancer (neratinib). Notably, the recent surge in preclinical covalent inhibitor pipelines across biotech and pharma highlights the methodological and technological advancements in covalent inhibitor research and development. Owing to the mechanism of action of this compound class, mass spectrometry is uniquely positioned as an ideal analysis tool for identification, optimization, and mechanistic characterization of covalent inhibitors across the entire developmental cycle of these therapeutics from library screening to clinical evaluation. IQ Proteomics leverages mass spectrometry to empower biotechnology and pharmaceutical companies as a contract research organization, and has developed a comprehensive, turn-key LC-MS based pipeline for supporting the preclinical development of covalent inhibitors. We present a case study exemplifying this LC-MS pipeline centered on the clinically approved KRAS inhibitor sotorasib. We first describe a high-throughput, proteome-wide cysteine ligandability assay ideally suited for initial identification of library hits and SAR evaluation of preliminary lead compounds, and demonstrate the complimentary utility of multiomics characterization (proteome expression profiling, PTM profiling, etc) to global cysteine profiling data. We further present an optimized targeted LC-MS (PRM) workflow for evaluating target-engagement both indirectly (disappearance of unmodified cysteine peptide) and directly (appearance of adduct peptide) for characterization of preclinical lead compounds over large numbers of in vitro and in vivo samples. We finally evaluate an isobaric multiplexed assay for rapid target engagement characterization of covalent inhibitors in complex matrices. Together, this suite of template assays represents a set of powerful tools for covalent inhibitor discovery, optimization, and therapeutic evaluation that empowers the oncology community as exciting covalent modalities continue to emerge with the potential to treat an increasing number of diseases. Citation Format: Kurt Baltier, Alison Erickson, Craig R. Braun, Ryan Kunz, Brian Erickson. An LC-MS toolbox for identifying and guiding the development of cysteine-targeted small molecule covalent 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 5754.
Abstract 5334: Proliferative signaling through the ras-erk pathway can be inhibited by the overexpression of dual-specific phosphatase genes in collaboration with other negative regulators of cell cycle progression in the acute myeloid cell line HL-60
Authors: Michael Roberts, Amelia Harper, Kishan Mangru, Katy Meta, Sophia Kovatsis, Jeffrey Forrester, Grace Crossland, Cuong Nguyen, Sher Bahadur
Journal: Cancer Research (2025)

Abstract Reversing or reprogramming malignant cells toward their normal gene expression patterns, without repairing their oncogenic mutations, can be accomplished in culture as demonstrated by the treatment of certain acute myeloid leukemia (AML) cell lines with phorbol esters, which through the activation of PKC results in cell cycle arrest, myeloid differentiation, and ultimately programmed cell death. Gene therapy continues to show promise in the development of new and effective cancer treatments. At its inception, replacing deficient tumor suppressor gene functions was an attractive goal and with the development of gene editing strategies, the repair of activated oncogenes is possible. Here we report the delivery and overexpression of negative regulators of oncogenic RAS signaling, through transfection, that provide tumor suppressor functions in the NRAS-driven cell line, HL-60, that inhibit their proliferative competency. Genes belonging to the dual-specific phosphatase family (DUSPs), including DUSP1, 5 and 6, along with RAS-ERK pathway inhibitors RASA1 and SPRY2, when transfected and overexpressed in HL-60 cells, affects decreases in phospho-ERK and Ki67 levels resulting in reduced proliferation. In combination with the overexpression of genes encoding the cyclin-CDK inhibitors, CDKN1A and CDKN2B, these anti-proliferative alterations are enhanced. While efficient strategies wait for the delivery of lacking tumor suppressor functions to cancer cells through targeted gene therapies, we propose candidate genes for reversing the proliferation program of RAS-driven AML cells. Citation Format: Michael Roberts, Amelia Harper, Kishan Mangru, Katy Meta, Sophia Kovatsis, Jeffrey Forrester, Grace Crossland, Cuong Nguyen, Sher Bahadur. Proliferative signaling through the ras-erk pathway can be inhibited by the overexpression of dual-specific phosphatase genes in collaboration with other negative regulators of cell cycle progression in the acute myeloid cell line HL-60 [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 5334.
Abstract 1466: Comprehensive analysis of breast and ovarian cancer-identified RAD51D variants
Authors: Kristie Darrah, Katherine Oppenheimer, Nicole Banks, Phoebe Parker, Ella Roberts, Gayatri Ganesan, Kara Bernstein
Journal: Cancer Research (2025)

Abstract The RAD51 paralogs are essential genes in coordinating the early steps of homologous recombination (HR)-mediated repair of DNA double strand breaks (DSBs). Currently, there are over 300 epidemiology studies linking a single mutation or polymorphism in one of the five canonical RAD51 paralogs to cancer predisposition and tumorigenesis. As one of the most frequently mutated RAD51 paralogs, mutations in RAD51D have been identified in 5% of hereditary ovarian cancers and pathogenic variants are associated with a 25% lifetime risk for breast cancer. We have uncovered more than 160 patient-identified missense variants in RAD51D, the majority of which are clinically classified as variants of unknown significance (VUS) and have little to no prior functional analysis. Herein, we have performed a comprehensive screen of all known missense RAD51D VUS identified in breast and ovarian cancer patients, identifying 7 potentially pathogenic variants which disrupt native protein interactions, reduce HR proficiency, and exhibit varying degrees of sensitivity to the typical chemotherapeutics used to treat HR-deficient (HRD) cancers. In defining the functional consequences of RAD51D VUS, we hope to inform formal clinical classification of these VUS in hopes of better estimating cancer risk and leverage precision therapeutic approaches for mutation carriers. Citation Format: Kristie Darrah, Katherine Oppenheimer, Nicole Banks, Phoebe Parker, Ella Roberts, Gayatri Ganesan, Kara Bernstein. Comprehensive analysis of breast and ovarian cancer-identified RAD51D variants. [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 1466.