tbuckley/cabot-search huggingface dataset:
Abstract 1642: Next trip: a promising CK1α-selective molecular glue degrader in MSS colorectal cancer
Authors: Hyunsun Jo, Hoon Choi, Hyemin Kim, Sohyun Park, Yelim Shin, Hyewon Shin, Yeonju Yoo, Dohee Yoon, Cheongbi Kim, Jinuk Kong, Goun Choi, Hadong Kim
Journal: Cancer Research (2025)

Abstract Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a critical role in cellular homeostasis. In previous studies, CK1α promotes p53 inactivation by regulating MDM2 and MDMX, and this mechanism may represent a promising anticancer target Indeed, many studies have been reported recently on the development of CK1α inhibitors and degraders as anticancer agents. We recently developed PIN5018, a selective CK1α inhibitor, and reported that it exhibits promising anticancer activity in acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Interestingly, PIN5018 showed anti-tumor activities in aggressive subtypes of AML patient xenograft (PDX) and ACC patient-derived xenograft (PDX) model. Strikingly, our CK1α MGD not only achieved complete remission in the ACC PDX model during drug administration but also maintained this effect for more than 20 days after discontinuation of the treatment. We conducted 2D or 3D in vitro activity assessments to screen for anticancer activity in additional candidate solid tumors. Based on these results, we focused our research on colorectal cancer (CRC). CRC is the third most prevalent cancer and a leading cause of cancer-related deaths worldwide. Over 80% of CRC patients are of the microsatellite stable (MSS) type, which, unlike the MSI group, represents a population with high unmet needs. For example, while chemotherapy and certain targeted therapies are available, they are applicable to only a subset of MSS patients, resulting in limited treatment options. From this perspective, we aimed to investigate the correlation between specific biomarkers and the in vitro and in vivo efficacy of PIN5018 in MSS CRC. As a result, we identified promising anticancer efficacy of PIN5018-mediated CK1α degradation under specific combinations of biomarker mutation conditions. Furthermore, we observed synergistic effects with PIN5018 when combined with standard of care (SoC) drugs. Taken together, these findings demonstrate the potential of our CK1α-selective MGD as a promising therapeutic candidate not only for AML and ACC but also for MSS CRC. Lastly, we are aiming for clinical entry by 2025 Q1. Citation Format: Hyunsun Jo, Hoon Choi, Hyemin Kim, Sohyun Park, Yelim Shin, Hyewon Shin, Yeonju Yoo, Dohee Yoon, Cheongbi Kim, Jinuk Kong, Goun Choi, Hadong Kim. Next trip: a promising CK1α-selective molecular glue degrader in MSS 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 1642.
Abstract 1194: Oral contraceptive use and risk of liver cancer: A prospective analysis in over 1.5 million women and systematic review and meta-analysis of observational studies
Authors: Cody Z. Watling, Siân Sweetland, Aika Wojt, Gisela Butera, Barry I. Graubard, Sarah Floud, Charles E. Matthews, Gillian Reeves, Katherine A. McGlynn
Journal: Cancer Research (2025)

Abstract Background: Oral contraceptive use has been suggested to increase the risk of liver cancer. While the International Agency for Research on Cancer concluded in 1999 that there was sufficient evidence of an association, this conclusion was based on case-control studies with few liver cancer cases. Current evidence of an association with all liver cancer or with its two major histologic types, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) remains unclear. Methods: The relationship between oral contraceptive use and liver cancer risk was examined using data from the Million Women Study (MWS) and the UK Biobank. Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). In addition, we conducted a systematic review and a meta-analysis of existing observational studies of oral contraceptive use and liver cancer. Results: A total of 2, 765 (median follow-up=21.4 years) and 191 (median follow-up=12.6 years) cases of liver cancer were observed in MWS and UK Biobank, respectively. No association was observed between ever- versus never-users of oral contraceptives and liver cancer risk in either the MWS or the UK Biobank (HR: 1.05, 95% CI: 0.97-1.13 and 1.08, 0.76-1.55, respectively). The meta-analysis of 23 observational studies, which included 5, 424 cases of liver cancer, found no evidence of an association between ever versus never oral contraceptive use and liver cancer; relative risk (RR):1.04, 0.98-1.11. In the meta-analysis of longer duration of use, women who used oral contraceptives for 4+ years had a slightly higher risk of total liver cancer (RR:1.10, 1.03-1.18) that was due to a small positive association with ICC (RR:1.11, 1.01-1.21). In contrast, there was no significant association between oral contraceptive use of 4+ years and HCC (RR: 1.07, 0.95-1.21). Conclusions: The totality of observational studies, including those that assessed associations by duration of use, suggests there is little or no association between oral contraceptive use and all liver cancer or HCC. There may be a small increased risk for ICC with longer duration of use, but confounding cannot be ruled out. Citation Format: Cody Z. Watling, Siân Sweetland, Aika Wojt, Gisela Butera, Barry I. Graubard, Sarah Floud, Charles E. Matthews, Gillian Reeves, Katherine A. McGlynn. Oral contraceptive use and risk of liver cancer: A prospective analysis in over 1.5 million women and systematic review and meta-analysis of observational studies [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 1194.
Abstract 271: BMH-21, an RNA polymerase I inhibitor provides a novel mechanism to target Δp53 and R248Wp53 driven pancreatic cancers
Authors: Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish Tripathi, Dae Joon Kim, Nirakar Sahoo, Tamer Oraby, Mohammad Moshahid Khan, Manu Sebastian, Subhash C. Chauhan, Bilal Bin Hafeez
Journal: Cancer Research (2025)

Abstract p53 mutations occur in 50-75 % of pancreatic cancer cases. p53 mutations promote the protein turnover and increase the dependence of cancer cells on ribosome biogenesis as compared to normal cells. We report that BMH-21, which is an RNA Polymerase I inhibitor can be used to inhibit the growth of Δp53 (truncated p53) and R248Wp53 driven pancreatic cancers. Our studies show that BMH-21 induced degradation of RPA194 (a catalytic subunit of RNA Polymerase I) has a very less cytotoxic effect on normal human pancreatic ductal epithelial cells. The p53 mutations in PanCa cells were found to play an important role in the recruitment of catalytic subunits of RNA polymerase I (RPA194 and RPA135) on ribosomal DNA (rDNA). BMH-21 decreases the recruitment of RPA194 on rDNA in Capan-2 cells that express p53 wild type and recruitment of both RPA194 and RPA135 on rDNA in MIA PaCa-2 cells that express R248W p53. We found that p53 wild type (WT) and mutant p53 physically interact with both the catalytic subunits of RNA polymerase I. BMH-21 induced degradation of RPA194 was found to expose Δp53 and R248Wp53 for ubiquitination. No ubiquitination of p53 WT was observed in BMH-21 treated Capan-2 cells. RNA polymerase inhibitors induce nucleolar stress that promotes p53 expression. BMH-21 induced ubiquitination of p53 prevents increases in expression of Δp53 and R248Wp53p53 which restricts the role of mutant p53s in the proliferation of PanCa cells. BMH-21 treatment reduces the growth of orthotopic xenograft pancreatic tumors in athymic nude mice with no observed toxicity. These findings suggest that BMH-21 is a promising therapeutic agent for treatment of PanCa. Citation Format: Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish Tripathi, Dae Joon Kim, Nirakar Sahoo, Tamer Oraby, Mohammad Moshahid Khan, Manu Sebastian, Subhash C. Chauhan, Bilal Bin Hafeez. BMH-21, an RNA polymerase I inhibitor provides a novel mechanism to target Δp53 and R248Wp53 driven pancreatic 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 271.
Abstract 2325: Anatomical genomic and transcriptomic analyses of Helicobacter pylori-driven gastric transformation
Authors: Yosuke Tanaka, Fumishi Kishigami, Toshihide Ueno, Shinya Kojima, Taiki Hashimoto, Yukinori Yamagata, Takaki Yoshikawa, Shigeki Sekine, Hiroyuki Mano
Journal: Cancer Research (2025)

Abstract Helicobacter pylori (HP) drives a chronic inflammation in the gastric mucosa, leading to atrophic gastritis, intestinal metaplasia (IM), and further culminating in gastric cancer. Oncogenesis by HP infection has been mainly attributed to epigenetic dysregulation, and recent advances in the understanding of clonal expansion have shed light on the mutational architecture of IM. However, these analyses have been performed separately, leaving our understanding fragmented. Furthermore, analyses on small-sized tissue cannot determine the spatial events in the entire stomach. These limitations of previous studies highlight the necessity for integrative genomic and transcriptomic analyses using the entire stomach samples. Here, we conducted exome sequencing on 295 crypts isolated from the gastric mucosa and 13 tumors of 13 individuals. In addition, we performed an extensive investigation of the spatial distribution of cell clones by characterizing crypts at 5 mm intervals from 360 areas in the pyloric region to the body regions throughout the stomach in 2 patients, which underwent RNA and exome sequencing. Mutational analyses revealed that the expansion of cell clones with gene mutations was accelerated by HP infection and smoking habits. Mutations in cancer-related genes, including MUC6, were positively selected in the crypts, specifically in the pylorus region. However, such gene sets mutated in the crypts were different from those in gastric cancer. Macroscopic spatial genomic analyses revealed the distribution profiles of these clones, and spatial transcriptomic examination further clarified an IM-specific expression profile with oncogenic potential. These results suggest a coordinated role for mutation acquisition and transcriptomic activation of the AP-1 signaling pathway or stem-like expression in HP-infected mucosa to drive oncogenesis. Our study elucidated the previously unknown coordinated relationship between clone formation and transcriptomic remodeling of HP-infected gastric mucosa. Given the oncogenic transcriptional circuit of IM, early Helicobacter pylori eradication, smoking cessation, and close monitoring of IM may be beneficial to reduce the opportunity of additional hazardous mutation acquisition. Citation Format: Yosuke Tanaka, Fumishi Kishigami, Toshihide Ueno, Shinya Kojima, Taiki Hashimoto, Yukinori Yamagata, Takaki Yoshikawa, Shigeki Sekine, Hiroyuki Mano. Anatomical genomic and transcriptomic analyses of Helicobacter pylori-driven gastric transformation [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 2325.
Abstract 658: Triple-negative breast cancer sensitization to anti-metabolite chemotherapy utilizing PARP inhibiting olaparib
Authors: Joshua C. Doloff, Amanda Rakoski, Abigail Yoo
Journal: Cancer Research (2025)

Abstract Triple Negative Breast Cancer (TNBC) is one of the most aggressive breast cancer subtypes as it grows faster than typical invasive carcinoma, leading to poor prognosis and an increased chance of recurrence. It lacks three key hormone receptors, estrogen, progesterone, and HER2 receptors, eliminating the efficacy of receptor-targeted therapies. The first line of treatment is the use of combination chemotherapies given at Maximum Tolerated Dosage (MTD) but this typically leads to higher toxicity and systemic side effects. We investigate Olaparib (OLA) and Gemcitabine (GEM) as a dual chemotherapy. OLA is an FDA-approved PARP inhibitor, facilitating single-stranded DNA breakage by preventing PARP from replacing excised nucleotides. GEM is an anti-metabolite that prevents cancerous cells from continuing mitosis and increasing apoptosis by taking the place of the nucleotide cytidine in the DNA during replication, leading to cell cycle arrest. We propose sensitizing TNBC to GEM by using OLA at lower doses than MTD while causing significant TNBC tumor cell death compared to the drug alone.We used EO771 cells (syngeneic to C57BL/6 mice) to evaluate GEM and OLA. Cells (100, 000/well) were plated in 24-well plates and treated with 0, 10, or 30 nM GEM, OLA, or combinations thereof. Crystal violet staining was used to visualize viable cells, which were quantified by absorbance at 550 nm. RNA extracted from 500, 000 cells/well in 6-well plates was analyzed via qPCR for stress and cytokine-related gene expression. GEM at 30 nM was more effective than at 10 nM, especially in combination with OLA (10 or 30 nM). Phase-contrast microscopy revealed significant cytotoxicity and cellular detachment with combined treatments, particularly GEM30/OLA10 and GEM30/OLA30. GEM 30/OLA 10 and GEM 30/OLA 30 showed the most significant cell death in response to combined chemotherapy. GEM 30/OLA 10 interestingly exhibited a slightly lower cell viability percentage than GEM 30/OLA 30. GEM30/OLA10 was the most effective combination tested, reducing TNF-α expression and cell viability while minimizing toxicity. The dual combinations suggest that GEM effectively disrupts DNA synthesis and drives single-stranded breakage. Future studies should include in vivo analyses of the tumor microenvironment, ELISAs for protein validation, and additional cell viability assays, such as MTT or XTT, to confirm these findings. Citation Format: Joshua C. Doloff, Amanda Rakoski, Abigail Yoo. Triple-negative breast cancer sensitization to anti-metabolite chemotherapy utilizing PARP inhibiting olaparib. [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 658.
Abstract 17: hiPSCs-derived <i>PTEN</i> deletion suppresses cardiomyocyte differentiation and beating
Authors: Thang Huu Nguyen, Chaeyong Jung, Sang Wook Park, Seung-Rock Lee
Journal: Cancer Research (2025)

Abstract Human-induced pluripotent stem cells (hiPSCs) have been increasingly used for cardiac tissue engineering and cell-based therapies for heart regeneration because they possess self-renewal capability in vitro and can differentiate into most cardiovascular cell types, including cardiomyocytes. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a potent tumor suppressor frequently being deficient in human cancer. It is also important for cardiac functions and embryonic development since the loss of PTEN induced embryonic lethality; however, the underlying mechanisms are not fully understood. Here, to understand the function of PTEN in cardiomyocyte differentiation, we generated PTEN deletion in hiPSCs by using CRISPR/Cas9 system. PTEN ablation suppressed cardiomyocyte differentiation, which was shown by decreases in cardiac markers cTNT and Myh6 compared with PTEN WT. Immunofluorescence staining and flow cytometry analysis using α-actinin and cTNT supported the suppression of cardiomyocyte differentiation induced by PTEN-/- hiPSCs. q-PCR analysis was performed using representative markers for differentiation steps including mesoderm, cardiac mesoderm, cardiac progenitor, and cardiomyocyte. PTEN-/- hiPSC decreased mesoderm markers (Brachyury, Dkk1, Fox C1) on the 2nd day of differentiation, suggesting that PTEN is important for early cardiac differentiation. Western blot analysis revealed that Gsk3β and mTOR phosphorylation levels were increased due to an activation of Akt, which may involve PTEN-/--induced mesoderm abnormality. In addition, PTEN deletion also inhibited cardiac beating capability, which may explain PTEN-/--induced embryonic lethality. Citation Format: Thang Huu Nguyen, Chaeyong Jung, Sang Wook Park, Seung-Rock Lee. hiPSCs-derived PTEN deletion suppresses cardiomyocyte differentiation and beating [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 17.
Abstract 394: Bridged proteolysis targeting chimera (PROTAC) enables degradation of the cyclin D undruggable protein
Authors: Yue Zhong, Yan Xiong, Hyerin Yim, Xiaobao Yang, Kwang-Su Park, Ling Xie, Poulikos Poulikakos, Xian Chen, Jing Liu, Jian Jin
Journal: Cancer Research (2025)

Abstract Proteolysis targeting chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While significant progress has been made in developing PROTACs for various protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins lacking small-molecule binders. To overcome this limitation, we present a novel PROTAC approach, termed bridged PROTAC. This approach utilizes a small-molecule binder of the target protein’s binding partner to recruit the protein complex into proximity with an E3 ubiquitin ligase, enabling the degradation of the target undruggable protein. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1. MS28 effectively degraded cyclin D1 prior to CDK4/6 and with superior degradation potency through recruiting the CDK4/6-cyclin D1 complex to the von Hippel-Lindau (VHL) E3 ligase. MS28 suppressed the proliferation of lung and breast cancer cells more effectively than CDK4/6 inhibitor and degraders. Notably, while triple negative breast cancer (TNBC) cell lines were mostly insensitive to CDK4/6 inhibitor and degrader treatment, they exhibited potent sensitivity to MS28. RNA-sequencing analysis revealed that while MS28 and CDK4/6 inhibitor and degrader shared downregulated genes associated with cell cycle regulation and DNA replication, MS28 upregulated a unique set of genes such as those involved in the unfolded protein response and endoplasmic reticulum stress pathway. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins, thereby offering invaluable chemical tools for the study of these proteins, and potentially delivering greater therapeutic efficacy than small-molecule inhibitors or degraders targeting alternative components within the signaling pathway. Citation Format: Yue Zhong, Yan Xiong, Hyerin Yim, Xiaobao Yang, Kwang-Su Park, Ling Xie, Poulikos Poulikakos, Xian Chen, Jing Liu, Jian Jin. Bridged proteolysis targeting chimera (PROTAC) enables degradation of the cyclin D undruggable protein [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 394.
Abstract 133: From waste to nutrient: ammonia's recycling by fibroblasts to sustain collagen production
Authors: Julien Guillard, Shan Cao, Marta Storl-Desmond, Brandon Faubert, Simon Schwörer
Journal: Cancer Research (2025)

Abstract Collagen and other extracellular matrix (ECM) proteins are highly abundant in tumors, including pancreatic and breast cancers, and are involved in tumor progression and therapy resistance. Given its amino acid composition, collagen production imposes unique biosynthetic demands on cancer-associated fibroblasts (CAFs), particularly a high need for proline. Understanding how CAFs meet the metabolic requirements for collagen synthesis could provide opportunities to modulate ECM production in cancer. CAFs synthesize proline from glutamine; however, glutamine and other nutrients are often depleted in poorly perfused tumors. How CAFs maintain collagen synthesis under such nutrient-limiting conditions remains unclear, and addressing this question may reveal unique metabolic vulnerabilities in cancer. Previous work from our laboratory showed that CAFs recycle extracellular lactate as an alternative carbon source to sustain non-essential amino acid (NEAA) biosynthesis for collagen production. However, NEAA synthesis also requires nitrogen, and how CAFs fulfill the nitrogen demands for NEAA synthesis under nutrient limitations remains poorly understood. To address this gap, this study aims to identify the nitrogen source used by CAFs for collagen production. To define the nitrogen source for collagen synthesis, we performed metabolic tracing of potential nitrogen donors using fibroblasts stimulated to deposit ECM in the presence of 15N-labeled nutrients. Stable isotope tracing with GC-MS was used to quantify 15N-labeled hydroxyproline in the decellularized and hydrolyzed ECM. We further used CRISPR/Cas9 to delete rate-limiting enzymes to elucidate the pathways involved. Our findings indicate that ammonia, a waste product of cellular metabolism, is recycled for NEAA biosynthesis. Ammonia’s contribution to collagen was dependent on the concentrations of glutamine and ammonia, and could rise to up to 50% of nitrogen in ECM hydroxyproline. All tested fibroblast cell lines exhibited similar ammonia-derived nitrogen labeling. Through genetic and chemical inhibition, we identified glutamate dehydrogenase (GDH) as a key enzyme in ammonia recycling via reductive amination. In conclusion, ammonia, a waste product of cancer metabolism, can be recycled by CAFs to sustain collagen production. This discovery highlights the metabolic plasticity of fibroblasts to maintain ECM synthesis under nutrient-limited conditions and offers new avenues for targeting adaptive pathways to reduce CAF-mediated pro-tumoral effects. Citation Format: Julien Guillard, Shan Cao, Marta Storl-Desmond, Brandon Faubert, Simon Schwörer. From waste to nutrient: ammonia's recycling by fibroblasts to sustain collagen production [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 133.