tbuckley/cabot-search huggingface dataset:
Abstract 3005: Discovery of a potential therapeutic mechanism for selected tumors via targeting PI3K and DDR pathways simultaneously with a novel orally available small molecule
Authors: Wyatt Wei Chen, Wenyu Xu, Yonghui Wang, Zhou Zhou
Journal: Cancer Research (2025)

The genomic instability and hyperactivation of PI3K pathway have been observed in many types of tumors. Targeting some of the key proteins among these pathways such as ATR or mTOR individually has been studied in many clinical trials with various small molecular drug candidates, but so far these efforts have failed to deliver therapeutic benefits to patients. One of the key challenges for targeting these targets is the lack of therapeutic window due to their significant toxicities in clinical trials. It has been evidenced that both PI3K and DDR pathways can be activated simultaneously in many tumor types. We hypothesize that targeting both mTOR and ATR simultaneously could generate synergistic effect to lower the toxicities while maintaining the efficacy in selected tumors. Through rational design, we discovered a novel orally available small molecule LIT-00814 which solely inhibits both mTOR and ATR with great selectivity against other kinases. In preclinical studies, LIT-00814 demonstrates much larger therapeutic window while maintaining good efficacy in selected tumor models with higher DDR mutations and PI3K pathway activities. A specific Akt1-S473 phosphorylation antibody LIT-A0001 has also been developed to precisely stratify patients in clinical trials which is critical to eliminate Akt2 and Akt3 signals and identify right patients for LIT-00814. The clinical phase I trials for LIT-00814 were initiated and the preliminary results hold promise to deliver beneficial therapy to selected cancer patients. In summary, we have discovered a novel orally available small molecule LIT-00814 targeting both mTOR and ATR with novel therapeutic mechanisms of action which could deliver beneficial therapy to selected cancer patients. Citation Format: Wyatt Wei Chen, Wenyu Xu, Yonghui Wang, Zhou Zhou. Discovery of a potential therapeutic mechanism for selected tumors via targeting PI3K and DDR pathways simultaneously with a novel orally available small molecule [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 3005.
Abstract 3095: Comparative analysis of WRN inhibitors HRO761 and VVD-133214 in a cancer cell panel: insights into MSI status-dependent drug responses
Authors: Lili Chai, Tingting Yang, Huawei Pan, Wei Liu, Zhengtai Li, Xiaojian Wang, Tj (Tiejun) Bing
Journal: Cancer Research (2025)

Abstract High-throughput screening of a cancer cell panel represents a pivotal instrument in the armamentarium of drug discovery and development. The sensitivity profiles of these cell lines serve as a cornerstone for the refinement of in vivo model systems and for the stratification of patient cohorts in clinical trials. Werner Syndrome RecQ Helicase (WRN), a member of the RecQ helicase family, is instrumental in the preservation of genomic integrity. Its multifaceted role encompasses DNA repair, replication, recombination, and telomere maintenance. WRN has garnered significant attention as a potential therapeutic nexus in oncology, particularly within the context of tumors exhibiting microsatellite instability (MSI). The synthetic lethality between WRN and MSI has been the subject of intensive research, demonstrating that WRN inhibition is selectively toxic to cancer cells harboring a high microsatellite instability (MSI-H) phenotype, which is a characteristic observed across a spectrum of malignancies, including colorectal, endometrial, and gastric cancers. The present investigation assesses the therapeutic potential of two advanced WRN inhibitors, HRO761 and VVD-133214, within a meticulously curated panel of cancer cells that display a continuum of MSI and microsatellite-stable (MSS) statuses, as well as HRO761 resistant cell lines. Employing cell viability assays, we conducted a comparative analysis of the growth-inhibitory effects of these compounds on MSI and MSS cell lines. Our data reveal a pronounced anti-neoplastic effect of both HRO761 and VVD-133214 in some MSI-H cell lines, juxtaposed with a diminished impact on MSS cell lines. Further, transcriptomic profiling elucidated discrete transcriptional landscapes modulated by each inhibitor, shedding light on their divergent pharmacological mechanisms. This study not only showcases our proficiency in high-throughput screening and bioinformatics but also contributes a wealth of knowledge regarding the MSI-dependent therapeutic responses to WRN-targeted agents, potentially informing future clinical strategies in cancer treatment. Citation Format: Lili Chai, Tingting Yang, Huawei Pan, Wei Liu, Zhengtai Li, Xiaojian Wang, Tj (Tiejun) Bing. Comparative analysis of WRN inhibitors HRO761 and VVD-133214 in a cancer cell panel: insights into MSI status-dependent drug responses [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 3095.
Abstract 3: TIP60 modulates colorectal cancer stemness through cd44 expression
Authors: Mohammad Asad, Sudhakar Jha
Journal: Cancer Research (2025)

Abstract Objective: To identify the functional role of TIP60 in regulating colorectal cancer (CRC) stemness. Materials and Methods: The HCT116 CRC cell lines were cultured in DMEM (high glucose) supplemented with 10% FBS. ShRNA-mediated depletion of TIP60 was generated using lentiviral vectors. To confirm TIP60 knockdown efficiency and CD44 expression levels, qPCR analyses were performed. For the colony formation assay, 1000 cells of HCT116 ShLuc control and ShTIP60 were seeded in 6-well plates and incubated for 11 days. For immunofluorescence staining, cells were grown on cover slips, fixed with 100% methanol for 20 minutes, and blocked with 3% BSA. They were then incubated with E-cadherin primary antibody at a 1:500 dilution and secondary antibody Alexa Fluor-488 at a 1:1000 dilution. Cells were mounted with Vectashield mounting medium containing DAPI. Spheroid culture was conducted in 96-well ultra-low attachment plates, with 100 cells of HCT116 ShLuc control and ShTIP60 seeded in each well and incubated for 7 days. The 3D invasion assay was performed in 96-well ultra-low round-bottom plates supplemented with 3D basement membrane extract (BME) invasion matrix. Findings: This study uncovered the pivotal role of HIV Tat-interactive protein (TIP60) in regulating CRC stemness. TIP60 depletion resulted in a significant decrease in cellular proliferation, highlighting the importance of TIP60 in CRC growth. Furthermore, TIP60 depletion altered colony formation, transitioning from densely packed formations to scattered spindle networks implying its involvement in the epithelial-mesenchymal transition (EMT). 3D culture models demonstrated that TIP60 is essential for spheroids formation, emphasizing its significance in promoting cancer stemness. TIP60-depleted cells exhibited enhanced invasion in a 3D BME invasion matrix, accentuating its crucial contribution to cellular invasiveness. Furthermore, we have identified that TIP60 undergoes liquid-liquid phase separation (LLPS). TIP60 harbors an intrinsically disordered region (IDR), which is essential for inducing LLPS in CRC. We have also discovered that TIP60 IDR regulates CRC stemness and EMT in CRC. In addition, the reduction of TIP60 was linked to a decrease in the expression of CD44, which is a crucial indicator for cancer stem cells (CSCs). Significantly, CD44 overexpression reinstated the efficiency of spheroid formation and reversed the EMT phenotype. Conclusions and Clinical Implications: Our findings suggest that TIP60 has CSC characteristics in CRC, and targeting TIP60 will offer a novel therapeutic approach against colorectal cancer stem cells. Citation Format: Mohammad Asad, Sudhakar Jha. TIP60 modulates colorectal cancer stemness through cd44 expression [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 3.
Abstract 3286: Targeting ALKBH5 to enhance the anti-tumor immunity of natural killer cells
Authors: Yuan Che, Tingting Tang, Zunsong Hu, Chao Shen, Zhenhua Chen, Wei Li, Kitty Wang, Lillian Sau, Ying Qing, Dong Wu, Keith Leung, Zhaoxu Xu, Xiaolan Deng, Jianjun Chen
Journal: Cancer Research (2025)

Abstract Natural killer (NK) cell-based immunotherapy is emerging to be a promising strategy to treat cancers due to its high safety profile. Compared with traditional chimeric antigen receptor (CAR) T therapy, NK cell-based therapy has much lower side effects such as cytokine release syndrome (CRS) or neurotoxicity. However, the limited persistence and lower levels of infiltration to the tumor microenvironment has impeded the outcomes for NK cell-based clinical trials. How to genetically engineer NK cells to a better priming activation state has yet to be explored. Here, we identify ALKBH5, a well-established RNA N6-methyladenosine (m6A) demethylase, as a key regulator that restricts NK cells cytotoxicity. Xenograft model studies using B16F10 and MC38 tumor cells demonstrated that tumor progression was dramatically inhibited upon Alkbh5 knockout (Alkbh5-/-) in the recipient mice. Single-cell RNA sequencing (scRNA-seq) revealed the enriched abundance of NK cells among tumor-infiltrating lymphocytes in Alkbh5-/- mice. Also, NK cells extracted from Alkbh5-/- spleen are hyperactivated, exhibiting enhanced cytotoxic function and proliferation rate, facilitating robust tumor suppression. Using MeRIP-seq, RIP-seq and lipid metabolomics, we demonstrated that Alkbh5 deficiency in NK cells reprogramed lipid metabolism pathway, enhancing the conjugation rate between NK cells and tumor cells. This increased synapse formation leaded to elevated release of perforin and granzyme, further improving NK cell killing capacity. Based on these findings, we genetically reprogrammed NK cells by conjugating anti-NK1.1 antibodies to lipid nanoparticles (LNPs) embedding Alkbh5-targeting oligonucleotides. Using the in vivo LNPs target delivery system, we want to explore whether this NK-based immunotherapy could inhibit tumor growth/progression in mice. Altogether, our findings uncover a previously unrecognized role for ALKBH5 in regulating NK cell cytotoxicity and proliferation, providing a new therapeutic strategy by targeting ALKBH5 in NK cell-based immunotherapies for solid tumors. Citation Format: Yuan Che, Tingting Tang, Zunsong Hu, Chao Shen, Zhenhua Chen, Wei Li, Kitty Wang, Lillian Sau, Ying Qing, Dong Wu, Keith Leung, Zhaoxu Xu, Xiaolan Deng, Jianjun Chen. Targeting ALKBH5 to enhance the anti-tumor immunity of natural killer 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 3286.
Abstract 1502: Hypoxia-driven genomic instability and EcDNA formation in lung cancer: insights from TRACERx
Authors: Natasha Sharma, Chris Bailey, Corentin Richard, Jeanette Kittle, Charles Swanton, Mariam Jamal-Hanjani, Nnennaya Kanu
Journal: Cancer Research (2025)

Abstract Tumors exhibit dynamic oxygen gradients, leading to hypoxia, which is linked to poor prognosis and genomic instability. The molecular features of hypoxia and their role in lung cancer outcomes remain unclear. Hypoxia has been linked to the forma on of fragile sites, resulting in chromosomal instability. Recent research has highlighted the generation of extrachromosomal DNA (EcDNA) because breaks. Genes amplified as EcDNA exist acentric circular structures capable driving rapid and significant genomic copy number amplifications. Inherent instability oncogene amplification on EcDNA provides tumor cells with a selective advantage adapting to changing environments. Thus, hypothesize that formation hypoxic tumors provide survivein unfavorable conditions like hypoxia contributes their poor prognosis. This study aims investigate impact disease outcomes formation. Furthermore, can act pressure, we examined its effects mutational burden, positive selection mutations, mutational signatures associated with hypoxia lung TRACERx cohort. TRACERx is multicenter prospective study collects samples from various regions of primary for high-depth next-generation sequencing. Analyzed bulk RNA sequencing data establish levels examine and EcDNA detection. Our preliminary findings reveal variability within between primary tumors, indicating inter- intratumoral hypoxia heterogeneity. High status correlates poorer overall disease-free survival in LUAD, but not LUSC. Additionally, presence significantly associated necrosis. Hypoxia increased circulating tumor (ctDNA) shedding (p &amp;lt; 0.05) and elevated whole-genome index (wgii) scores. High-hypoxia exhibit alterations, tumor suppressor b2m, increased expression immunosuppressive chemokines (cxcl8, ccl8, cxcl10). Furthermore, extrachromosomal was detected both LUAD average" hypoxia scores were -0.006 EcDNA-positive compared -0.248 EcDNA-negative samples, highlighting prevalence tumors. In conclusion, shows existence heterogeneity of hypoxia within cohort association clinical outcomes. We highlight link hypoxia, detection, the increased expression contributing a tumor microenvironment. Citation Format: Natasha Sharma, Chris Bailey, Corentin Richard, Jeanette Kittle, Charles Swanton, Mariam Jamal-Hanjani, Nnennaya Kanu. Hypoxia-driven genomic instability and EcDNA formation in lung cancer: insights from TRACERx [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 1502.
Abstract 3530: Utilizing a humanized HLA-A2.1 mouse model for non-clinical studies of mRNA vaccines
Authors: Leila Kokabee, Zhenlan Niu, Jing Guo, Shuaiqiang Zhang, Zhiyuan Shen, Hui Xu
Journal: Cancer Research (2025)

Abstract Substantial genetic discrepancies exist between the major histocompatibility complex (MHC) systems of animals and the human leukocyte antigen (HLA) system. The utilization of HLA humanized mouse model systems constitutes a superior methodology for examining fundamental mechanisms associated with HLA-A-related vaccine development and HLA-A-restricted immune responses against diseases such as infections and cancers in humans. To study both in vitro and in vivo the requirements for shaping an effective T cell response against clinically relevant cancer targets such as NY-ESO-1, WT1 and other newly discovered targets, Biocytogen generated a C57BL/6 background HLA-A2.1 humanized mouse model that is restricted to the human HLA-A2. This humanized mouse model was utilized to evaluate immune responses to a variety of cancer peptide and mRNA vaccines, including analyses of immune cell populations, cytokine production, and in vivo anti-tumor efficacy. Immunoprofiling analysis of this novel humanized HLA-A2.1 mouse strain revealed that the introduction of the HLA-A2.1 gene significantly influences the immune cell composition in these humanized mice. Following vaccination with various cancer-specific epitopes, HLA-A2.1-restricted, epitope-specific cytotoxic T lymphocytes (CTLs) were induced in the B-HLA-A2.1 mouse model. Furthermore, we established an mRNA vaccination treatment model in B-HLA-A2.1 mice, demonstrating a synergistic antitumor effect when combined with the mRNA vaccine. These findings indicate that the B-HLA-A2.1 mouse model serves as a powerful research tool, not only for investigating HLA-A2.1-restricted CTL responses but also for the preclinical evaluation of vaccines. We have established a promising preclinical research model using HLA-A2.1 humanized mice. This model could accelerate the identification of novel HLA-A2.1-restricted epitopes and facilitate vaccine development, while also supporting the study of HLA-A2.1-restricted responses against cancers in humans. Citation Format: Leila Kokabee, Zhenlan Niu, Jing Guo, Shuaiqiang Zhang, Zhiyuan Shen, Hui Xu. Utilizing a humanized HLA-A2.1 mouse model for non-clinical studies of mRNA vaccines [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 3530.
Abstract 3792: Antigen and therapeutically relevant T cell molecular checkpoints control B cell heterogeneity and function to deliver anti-tumor immunity
Authors: Daniel P. Hollern
Journal: Cancer Research (2025)

Abstract B cells predict survival and treatment success across cancers. Yet, gaps in the known mechanisms that regulate B cell function in cancer imparts challenges for therapeutic utilization. In our lab’s studies of B cell responses to aggressive mouse solid tumors, we find that specific qualities of antigen and key signals from CD4+ T cells to B cells mediates the composition and function in B cell responses to tumors. Using mouse models to track antigen and antigen-specific B cells in tumor draining lymph nodes, we find that neoantigen solubility or being membrane bound along with the degree of BCR-antigen affinity shapes B cell mediated tumor control, heterogeneity, and the capacity for B cell mediated epitope spreading. Testing how B cell responses to antigen are shaped immunetherapy, we show that anti-PD1 and anti-CTLA4 therapies elicit CD4+ T cell IL21 and CD40Lg signals; ultimately mediating the composition of B cell subsets and function. Expanding on CD40 ligand function with translationally relevant CD40 agonists, which mimick CD4+ T cell CD40 ligand, we find that this checkpoint can elicit anti-tumor extrafollicular memory B cells that use CD86 signals to cause CD8+ T cells to become cytotoxic and mediate tumor control. Thus, our findings advance the understanding of how B cells are regulated and function to provide durable anti-tumor immune responses. Citation Format: Daniel P. Hollern. Antigen and therapeutically relevant T cell molecular checkpoints control B cell heterogeneity and function to deliver anti-tumor immunity [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 3792.
Abstract 2973: Discovery of novel synthetic lethal targets for effective and safe colorectal cancer therapies
Authors: Andrzej Mazan, Marcin Duleba, Eliza Zimolag, Joanna Szuszkiewicz, Marcin Serocki, Joanna Krawczyk, Oleksii Bryzghalov, Agata Stachowicz-Walaszek, Izabella Wieckowska, Marcelina Chmiel, Alexander Kurzejamski, Barbara Lipert, Katarzyna Sarad, Michal Mikula, Rafal Dziadziuszko, Tomasz Rzymski, Andrew Thomason, Krzysztof Brzozka
Journal: Cancer Research (2025)

Colorectal cancer (CRC) poses a significant global health burden, highlighting the urgent need for innovative and effective treatment options. This study focuses on the discovery and validation of novel therapeutic targets, particularly synthetic lethal (SL) interactions, to exploit specific genetic vulnerabilities in CRC cells and enable the development of safer and more effective therapies. We employed a comprehensive strategy integrating healthy cells, genetically engineered isogenic cancer models derived from human intestinal stem cells (hISCs) with patient-derived xenografts (PDXs) and primary cell cultures. Using CRISPR/Cas9 technology, we introduced key CRC-associated mutations into the hISCs to replicate disease-specific contexts. Transcriptome profiling, coupled with machine learning, validated these models as robust, clinically relevant representations of tumor biology by aligning them with clinical datasets. Genome-wide CRISPR/Cas9 screenings conducted across the isogenic and patient-derived models revealed actionable vulnerabilities, including the identification of genes that are synthetically lethal with APC and KRAS mutations. Discovered SL targets were rigorously validated in vitro and in vivo using patient-derived cells with matching mutational profiles. This integrative approach bridges preclinical and clinical research, ensuring translational relevance. By identifying and validating SL targets tailored to CRC mutational landscapes, we provide a robust foundation for the development of novel treatment options for CRC patients. Citation Format: Andrzej Mazan, Marcin Duleba, Eliza Zimolag, Joanna Szuszkiewicz, Marcin Serocki, Joanna Krawczyk, Oleksii Bryzghalov, Agata Stachowicz-Walaszek, Izabella Wieckowska, Marcelina Chmiel, Alexander Kurzejamski, Barbara Lipert, Katarzyna Sarad, Michal Mikula, Rafal Dziadziuszko, Tomasz Rzymski, Andrew Thomason, Krzysztof Brzozka. Discovery of novel synthetic lethal targets for effective and safe colorectal cancer therapies [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 2973.
Abstract 2745: Identification of a selective and orally bioavailable BPTF PROTAC with anti-tumor activity in SWI/SNF mutant lung cancer
Authors: Wen Yan, Jay Chung, Denis E. Reyna, Dan Sherman, Sabrian Li, Sara Linker, John Lapek, Soweto Thomas, Jennifer Pizzano, Elizabeth Bortolon, Sonja Brun, Steve Kaiser, Sylvie Sakata, Ian Taylor, Jennifer Cantley, Adam Gilbert, Thomas Paul
Journal: Cancer Research (2025)

Abstract BPTF is a bromodomain and PHD finger domain-containing protein that serves as a scaffolding subunit of the ISWI family member NURF chromatin remodeling complex. Together with interchangeable catalytic subunits SMARCA1 and SMARCA5 and additional subunits RBBP4, RBBP7, the NURF complex catalyzes ATP to slide nucleosomes on DNA, exposing or occluding transcription factor binding sites, leading to transcriptional activation or repression. Dysregulation of BPTF-containing NURF complexes disrupts gene expression and contributes to oncogenesis. BPTF overexpression is observed in various cancers and correlates with poor survival. Here we report the discovery of potent and selective BPTF heterobifunctional protein degraders A123497 and A126329 utilizing BPTF bromodomain ligand NVS-BPTF-1. While BPTF bromodomain ligands are inactive across a panel of lung cancer cell lines, BPTF degraders demonstrate potent anti-tumor activity in a subset of SCLC and NSCLC models, recapitulating the genetic dependency observed in CRISPR inhibition studies. Anti-tumor activity of BPTF degraders exists in a subset of lung cancer cell line models enriched in mutations in the SMARCA2/4 catalytic subunit of SWI/SNF chromatin remodeling complex. BPTF degradation leads to loss of protein stability and chromatin binding to additional NURF complex members including catalytic subunits SMARCA1 and SMARCA5 and chromatin accessibility changes at specific genes. Unique chromatin accessibility changes observed with BPTF degraders in cell lines harboring mutant SWI/SNF suggest interplay between chromatin remodeling functions of NURF and SWI/SNF complexes. We present optimization of BPTF degraders for in vivo dosing further demonstrating the therapeutic potential for targeting BPTF-containing NURF complex in cancer. Citation Format: Wen Yan, Jay Chung, Denis E. Reyna, Dan Sherman, Sabrian Li, Sara Linker, John Lapek, Soweto Thomas, Jennifer Pizzano, Elizabeth Bortolon, Sonja Brun, Steve Kaiser, Sylvie Sakata, Ian Taylor, Jennifer Cantley, Adam Gilbert, Thomas Paul. Identification of a selective and orally bioavailable BPTF PROTAC with anti-tumor activity in SWI/SNF mutant lung 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 2745.