tbuckley/cabot-search huggingface dataset:
Abstract 6987: MYC condensate-modulating small molecules demonstrate robust antitumor activity in animal models of ovarian cancer and other solid tumors
Authors: Ann Boija, Bede Portz, Yingda Ye, Jian-Guo Ren, Thomas Durand-Reville, Kip West, Isaac Klein
Journal: Cancer Research (2025)

Abstract The transcription factor MYC is a critical driver of cancer, implicated in 70% of malignancies and amplified in approximately 30% of ovarian cancers, where it contributes to aggressive tumor progression. Despite its pivotal role in oncogenesis, MYC has eluded traditional structure-based drug discovery efforts due to the absence of well-defined drug binding sites and its dependence on highly dynamic interactions. Here, we are deploying condensate biology and phenotypic screening to identify and optimize small molecule condensate modulators (c-mods) to modify MYC oncogenic function. In vitro, MYC c-mods dissolve MYC nuclear condensates, selectively repress MYC-driven gene expression, and induce cell killing in a spectrum of ovarian cancer and esophageal cancer cell lines. Advanced MYC c-mods optimized using Dewpoint’s AI/ML-powered end-to-end platform are orally bioavailable and yield tumor stasis and regression in in vivo models of ovarian cancer at tolerated daily doses. We demonstrate that the antitumor activity of the MYC c-mods extends to additional in vivo models from multiple indications and correlates with repressed MYC activity in tumors. Citation Format: Ann Boija, Bede Portz, Yingda Ye, Jian-Guo Ren, Thomas Durand-Reville, Kip West, Isaac Klein. MYC condensate-modulating small molecules demonstrate robust antitumor activity in animal models of ovarian cancer and other solid tumors [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 6987.
Abstract 6606: Genomic features of histological and molecular subtypes in Japanese ovarian cancer
Authors: Osamu Gotoh, Norio Tanaka, Tomoko Kaneyasu, Seiichi Mori, Tetsuo Noda
Journal: Cancer Research (2025)

Abstract Ovarian cancer is an intractable disease and comprises a number of histological subtypes that are associated with clinical characteristics such as therapeutic efficacy and likelihood of relapse. Since ovarian cancer exhibits heterogeneity even within a same histological subtype, it is critical to develop a complementary classification framework, in which clinicopathological and biological features are associated with each subtype. Previously, for endometrial cancer, a molecular subtyping scheme based on genomic features was developed by The Cancer Genome Atlas (TCGA) and the scheme has been currently integrated into the system of 2020 WHO classification of Female Genital Tract tumor. A similar classification scheme has been needed developed for ovarian cancer diagnosis for further clinical stratification. Whereas genomic features can be utilized for this purpose because of the tight relationship with clinical manifestations, previous large-scale genomic studies of ovarian cancer have been conducted mainly with high-grade serous (HGS) histology, a major histological subtype in Caucasian. The remaining histologies exemplified by clear cell carcinoma, which is uniquely prevalent in the East Asian population, have not been covered by these studies, and therefore genomic features that can be utilized for molecular subtyping have not been well characterized for non-HGS ovarian cancer. To link genomic features with histological subtypes and to obtain wealthy information for further potential genomic stratification, we conducted genome sequencing analyses of 1,412 Japanese ovarian cancers across 6 major histotypes (clear cell, high-grade serous, endometrioid, mucinous, carcinosarcoma and sex cord-stromal). Using copy number information derived from sequenced data, we identified a novel copy number subtype, which is uniquely associated with clinicopathological and genomic attributes. The results will be presented focusing on the genomic features including germline mutations, somatic driver events and mutational signatures, in association with histological and molecular subtypes. Citation Format: Osamu Gotoh, Norio Tanaka, Tomoko Kaneyasu, Seiichi Mori, Tetsuo Noda. Genomic features of histological and molecular subtypes in Japanese 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 6606.
Abstract 6892: Ribonucleotide reductase is a potential therapeutic target in colorectal cancer
Authors: Federica Invrea, Consalvo Petti, Claudio Isella, Enzo Medico
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness and treatment response. Primary and acquired resistance limit the efficacy of available treatments, and identification of new therapeutic targets is needed to further improve patients’ outcomes. To identify actionable targets, we performed a “drop-out” loss-of-function screening with an shRNA library covering 200 drug-target genes in nine different CRC cell lines, covering the whole spectrum of molecular subtypes of CRC. Multiple screening hits were found. Among them RRM1, encoding a member of the ribonucleotide reductase complex and targeted by the FDA-approved drug clofarabine, was found to be non-dispensable in all cell lines. In vitro drug efficacy studies confirmed sensitivity to clofarabine of most CRC cell lines. In vivo testing on a CRC cell line xenograft confirmed substantial growth inhibition by clofarabine. These results unveil a possible therapeutic opportunity in colorectal cancer. Citation Format: Federica Invrea, Consalvo Petti, Claudio Isella, Enzo Medico. Ribonucleotide reductase is a potential therapeutic target in 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 6892.
Abstract 7275: A novel PD-1, IL12Rβ1 and IL12Rβ2 humanized mouse model for evaluating the combined efficacy of anti-tumor therapies
Authors: Jade Hsu, Linlin Wang, Fengxing Gu, Meiqi Zhang, Jing Guo, Xiaofei Zhou
Journal: Cancer Research (2025)

Abstract PD-1 is an inhibitory immune checkpoint that reduces T cell activity by binding to its ligand PD-L1, which facilitates immune evasion in the tumor microenvironment. In recent years, targeting PD-1 has become a key component of cancer immunotherapy. Interleukin-12 (IL-12) serves as a crucial regulatory factor in both innate and adaptive immunity; it promotes cell proliferation, activates cytotoxic lymphocytes and natural killer (NK) cells, boosts the production of interferon (IFN)-γ, and supports cell differentiation, thereby enhancing the generation of TH1-related immunoglobulins. Given its role in pro-inflammatory responses and immune modulation, IL-12 has the potential to convert tumors from a "cold" state to a "hot" state. Therefore, the combination of IL-12 and PD-1 inhibitors represents a promising strategy for advancing cancer immunotherapy. Biocytogen has developed B-hPD-1 plus/hIL12RB1/hIL12RB2 mice by breeding humanized PD-1mice with humanized IL12RB1 and IL12RB2 mice. To validate the PD-1 expression, splenocytes were collected from C57BL/6 mice and homozygous B-hPD-1 plus/hIL12RB1/hIL12RB2 mice stimulated with anti-mouse CD3ε antibody in vivo for 24 hrs. Mouse PD-1 was only detectable in C57BL/6 mice. Human PD-1 was exclusively detectable in homozygous B-hPD-1 plus/hIL12RB1/hIL12RB2 mice, but not in C57BL/6 mice. To validate the functionality of the humanized IL12Rβ1 and IL12Rβ2 receptor complex, CD4+ T cells sorted from splenocytes of C57BL/6 and homozygous B-hPD-1 plus/hIL12RB1/hIL12RB2 mice were stimulated with human IL-12 in vitro, and IFN-γ production was detected by ELISA. Mouse IFN-γ were both increased after responsiveness to mIL-12 in C57BL/6 mice and homozygous B-hPD-1 plus/hIL12RB1/hIL12RB2 mice. Mouse IFN-γ were increased after responsiveness to hIL-12 in homozygous mice but not in wild-type mice. In summary, the PD-1, IL12RB1, and IL12RB2 genes have been successfully humanized in B-hPD-1 plus/hIL12RB1/hIL12RB2 mice, allowing us to assess the combined efficacy of anti-tumor drugs. Citation Format: Jade Hsu, Linlin Wang, Fengxing Gu, Meiqi Zhang, Jing Guo, Xiaofei Zhou. A novel PD-1, IL12Rβ1 and IL12Rβ2 humanized mouse model for evaluating the combined efficacy of anti-tumor 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 7275.
Abstract 3150: Utilizing the HiBiT system to identify CARM1 degraders for targeted cancer therapy
Authors: Megan Bacabac, Fabao Liu, Eui-Jun Kim, Isaac Hayes, Yidan Wang, Weiping Tang, Tim S. Bugni, Wei Xu
Journal: Cancer Research (2025)

Abstract Coactivator-associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family that asymmetrically dimethylates proteins on arginine residues. Methylation of BAF155 by CARM1 in triple-negative breast cancer (TNBC) drives cancer metastasis. Amplification and overexpression of CARM1 has been observed in a variety of cancers, including breast cancer, and its overexpression correlates with poor prognosis. Potent small molecule inhibitors for CARM1 have been developed but the effects of inhibiting CARM1 differ from the effects of knocking out (KO) CARM1 in cancer cells. CARM1 KO, but not CARM1 inhibition, decreases cancer cell proliferation. This implies that CARM1 also has non-enzymatic roles in driving cancer progression which necessitates the development of small molecule degraders of CARM1 to inhibit both structural roles and enzymatic activity. We have developed CARM1-specific proteolysis targeting chimeras (PROTACs), which contain a CARM1 ligand (TP-064), a rigid chemical linker, and an E3 ligase ligand (von-Hippel Lindau) to target CARM1 for proteasomal degradation. We characterized the degradation activity of the best compound, 3b, which has a DC50 of 8.1 nM and a Dmax of 97%. While PROTAC 3b is potent and selective, many challenges remain in using PROTACs in clinical settings. There are still no PROTACs that have received FDA-approval. A possible way to overcome the potential toxicity and side effects of chemically synthesized drugs is to utilize naturally occurring products. We generated a breast cancer cell line containing HiBiT-tagged CARM1 to perform high-throughput unbiased screening of 1408 natural products. Two natural product fractions, named 5_9 and 10A, decreased luciferase signal and CARM1 protein levels by Western blot. Treatment with either natural product did not impact the protein levels of another PRMT family member, PRMT6. Ongoing studies will determine the biological consequences of 5_9 and 10A on breast cancer cell lines and organoids. CARM1 PROTACs and natural products may be developed as therapeutic agents for targeting CARM1-driven cancers more effectively than currently available inhibitors. Citation Format: Megan Bacabac, Fabao Liu, Eui-Jun Kim, Isaac Hayes, Yidan Wang, Weiping Tang, Tim S. Bugni, Wei Xu. Utilizing the HiBiT system to identify CARM1 degraders 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 3150.
Abstract 5387: Modeling physiological lipid availability of tumors to improve in vitro studies of cancer cell lipid metabolism
Authors: Mete E. Ozgurses, Vipin S. Rawat, Kelly O. Conger, Huiping Zhao, Patrick B. Jonker, Alexander Muir, Jonathan L. Coloff
Journal: Cancer Research (2025)

Lipids are highly crucial in cellular physiology and pathology. They are the main structural components of cellular membranes and play critical roles in metabolism, signaling, and other core processes. Many studies of lipid metabolism, both in cancer and other fields, rely on the results of in vitro tissue culture experiments. Generally, in vitro culture systems use media containing non-physiological levels of nutrients, including high levels of critical nutrients like glucose and glutamine. Recently, several groups have generated culture media with physiological levels of polar metabolites, which can correct some tissue culture-related artifacts. However, these new-generation media still use traditional serum and still represent severe lipid starvation conditions. In lipid-deprived environments, cells respond by activating the sterol regulatory element binding protein (SREBP) pathway, a transcriptional regulator of global lipid metabolic gene expression. Our SREBP transcription factor signature scores comparing human tumor samples to established cancer cell lines growing in TM showed dramatic activation of SREBP in cell lines relative to tumors, supporting traditional tissue culture being a highly lipid-starved environment. We hypothesized that these lipid-starved conditions impact cancer cell behavior in vitro and that developing a more physiological lipid medium will maintain more accurate cell metabolic characteristics. To study this, we have generated two new physiological lipid media - one that mimics lipid levels found in human plasma (HSLM) and one that mimics the lipid levels found in the tumor microenvironment (TILM). The lipidomic analysis confirmed that HSLM closely resembles the lipidome of human serum, while TILM more accurately aligns with the lipid profile of tumor interstitial fluid (TIF). We found that cell lines were unable to survive when cultured in HSLM. However, cancer cell lines adapted to TILM, reduced de novo lipogenesis and proliferation rate and had a similar fatty acid profile to in vivo mouse tumors compared to TM. In the future, we would like to comprehensively study how cells change their metabolism, signaling, and lipid profile to see whether cells cultured in TILM better represent primary tumor metabolism. Citation Format: Mete E. Ozgurses, Vipin S. Rawat, Kelly O. Conger, Huiping Zhao, Patrick B. Jonker, Alexander Muir, Jonathan L. Coloff. Modeling physiological lipid availability of tumors to improve in vitro studies of cancer cell lipid metabolism [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 5387.
Abstract 6177: Deciphering the molecular determinants of testosterone paradox in prostate cancer
Authors: Abhishek Shetty, Lillian Wilson, Deven Topiwala, Vaishnavi Anand, Zhen Wong, Yuhan Yang, Chandana Kruthiventi, Sai Harshitha Dakoor, Virginia Bencosme, Taylor Blanco, Boan Yang, Sayyada Kazim, Olutosin Owoyemi, Nathaniel Brennen, Eugene Shenderov, Michael Carducci, Samuel Denmeade, Sushant Kachhap
Journal: Cancer Research (2025)

Abstract Androgen deprivation therapy (ADT) is the mainstay of PC treatment for lethal, recurrent and metastatic prostate cancer (PCa). Although the initial response rate to ADT is high, the therapy invariably fails as cancer cells become resistant to therapy and progress into a castration-resistant stage called castration-resistant prostate cancer (CRPC). Based on a long-standing paradoxical observation that the growth of PCa could be inhibited by supraphysiologic testosterone (SupraT) treatment, we devised a therapy called the bipolar androgen therapy (BAT) to treat the CRPC. BAT involves a rapid cycling of testosterone between two polar extremes from supraphysiological to near castrate levels with each cycle lasting 28 days. Following the significant clinical efficacy of BAT in a subset of men with metastatic CRPC, we elucidated that SupraT can induce a non-apoptotic cell death called ferroptosis and activate innate immune genes in SupraT-sensitive PCa cells. The current study aims to identify molecular determinants of SupraT-induced cell death and immune activation. This study sheds light on the molecular mechanisms involved in the BAT therapeutic response. Understanding and characterizing the molecular determinants of PC response to BAT is crucial as it will help us stratify patients who would benefit from the therapy and also devise novel combination therapies with BAT including immunotherapeutics, for an enhanced clinical outcome. Citation Format: Abhishek Shetty, Lillian Wilson, Deven Topiwala, Vaishnavi Anand, Zhen Wong, Yuhan Yang, Chandana Kruthiventi, Sai Harshitha Dakoor, Virginia Bencosme, Taylor Blanco, Boan Yang, Sayyada Kazim, Olutosin Owoyemi, Nathaniel Brennen, Eugene Shenderov, Michael Carducci, Samuel Denmeade, Sushant Kachhap. Deciphering the molecular determinants of testosterone paradox in prostate 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 6177.
Abstract 6984: Discovery of selective SMARCA2 inhibitors for the treatments of SMARCA4 mutated cancers
Authors: Seong Heon Kim, Hyuntae Kim, Sukho Lee, Minou Choi, Jong Woo Park, Hyosun Choi, Goeun Yang, Daehoon Kim, Doo-Young Kim, Sunhee Lee, Min Ah Park
Journal: Cancer Research (2025)

Abstract BRM and BRG (SMARCA2/4) are two mutually exclusive catalytic ATPase subunits of the BAF complexes. SMARCA4 is frequently mutated in multiple cancers, including about 10% of non-small cell lung cancer (NSCLC). As a result, SMARCA4 deficient cancer cell becomes more dependent on its paralog, SMARCA2, for their survival. Consequently, a selective inhibitor targeting SMARCA2 is a potentially effective therapeutic option for SMARCA4-mutant cancers. We identified HD-10991 and HD-11030 as selective SMARCA2 inhibitors and evaluated their potency in SMARCA2 and SMARCA4 biochemical assays, as well as in Cell Titer-Glo assays using melanoma and NSCLC cell lines. HD-10991 and HD-11030 effectively inhibited SMARCA2 activity with single-digit nanomolar potency by binding to the ATPase domain. Both compounds demonstrated excellent selectivity, showing over 30-fold greater potency against BRM compared to BRG1 in chromatin remodeling assays. HD-10991 and HD-11030 possess desirable drug-like properties for oral administration, including favorable physicochemical characteristics and pharmacokinetic profiles. Systemic exposure through oral administration resulted in dose-dependent anti-tumor effects, consistently leading to tumor growth arrest and regression in SMARCA4-mutant xenograft models, such as SK-MEL-5 and A549 CDX models. Additional in vitro and in vivo studies in SMARCA4-mutant cell lines are ongoing to support the further development of these compounds. These findings, highlighting the anti-tumor efficacy and promising drug-like properties of HD-10991 and HD-11030, underscore their potential as candidates for preclinical studies aimed at therapeutic intervention for patients with SMARCA4-mutant cancers. Citation Format: Seong Heon Kim, Hyuntae Kim, Sukho Lee, Minou Choi, Jong Woo Park, Hyosun Choi, Goeun Yang, Daehoon Kim, Doo-Young Kim, Sunhee Lee, Min Ah Park. Discovery of selective SMARCA2 inhibitors for the treatments of SMARCA4 mutated cancers [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 6984.
Abstract 7084: Multi-omics information from tumor-derived extracellular vesicles enables biomarker discovery and early detection in non-small cell lung cancer
Authors: Kelley Van Vaerenberghe, Margie Kinnersley, Claire Seibold, Tre Blohm, Riley Kemp, Sean Lodmell, Amanda Mast, Tia Seibold, Rachel Short Miller, Katie Havranek
Journal: Cancer Research (2025)

Abstract Liquid biopsy plays an increasingly influential role in clinical decision making by supporting earlier cancer detection, diagnosis, patient stratification, and treatment monitoring. The most common approaches utilize cell-free circulating tumor DNA or circulating tumor cells in the peripheral blood of cancer patients. However, these methods are impeded by miniscule analyte abundance leading to unfavorable signal to noise ratios. As a promising alternative, extracellular vesicles (EVs) have emerged as a complementary liquid biopsy analyte. EVs are cell-derived lipid membrane encapsulated particles carrying diverse protein, nucleic acid, and metabolite cargos. Blood plasma of cancer patients contains EVs from healthy cells and tissues throughout the body, but also contains a population of EVs derived directly from tumor tissue. These tumor-derived EVs (TDEVs) serve as rich sources of insight into tumor biology and disease pathology. To detect TDEVs amongst background noise, we have developed a clinically applicable, multi-omic EV subpopulation interrogation pipeline that robustly profiles TDEVs in blood plasma. We have demonstrated the ability of the pipeline to enrich cancer markers and detect activation of pathways driving oncogenesis across several different cancers, including non-small cell lung cancer (NSCLC). There is a particularly compelling need for liquid biopsy-based solutions in early detection and screening applications, when patient adherence to standard of care screening regimens could be improved by simplifying the procedure to a routine blood draw. Here, we have applied our EV-omic pipeline in combination with machine learning in a cohort of NSCLC patients to robustly identify Stage I and II disease using blood-based EV proteomic and transcriptomic signatures. Biomarker profiles found to be most important for patient stratification combine markers known to be relevant in tumor tissue along with novel features. This work highlights our EV subpopulation technology and its ability to address the major challenge of early cancer detection in liquid biopsy. Citation Format: Kelley Van Vaerenberghe, Margie Kinnersley, Claire Seibold, Tre Blohm, Riley Kemp, Sean Lodmell, Amanda Mast, Tia Seibold, Rachel Short Miller, Katie Havranek. Multi-omics information from tumor-derived extracellular vesicles enables biomarker discovery and early detection in non-small cell 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 7084.