tbuckley/cabot-search huggingface dataset:
Abstract 426: Dual CDK4/6 and CDK7 inhibition: A synergistic strategy to overcome resistance and enhance anti-tumor immunity in breast cancer
Authors: Sungsoo Kim, Eugene Son, Haram Park, Minah Kim, Hee Won Yang
Journal: Cancer Research (2025)

Abstract Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved outcomes for patients with hormone receptor-positive (HR+) breast cancer. However, resistance to CDK4/6i limits their long-term efficacy, and their monotherapy has shown limited impact in triple-negative breast cancer (TNBC). Here, we present a novel therapeutic strategy combining CDK4/6i and CDK7 inhibitors (CDK7i) to address these limitations. Using a comprehensive suite of approaches—including live-cell imaging, RNA sequencing, and preclinical tumor models—we demonstrate the efficacy of this combination in overcoming drug resistance and enhancing anti-tumor immunity.Kinetic analyses revealed that CDK7i primarily suppresses RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance. Mechanistically, CDK7i prevents E2F activity amplification following retinoblastoma protein (Rb) degradation, a critical step in the development of resistance. Consequently, combining CDK4/6i and CDK7i synergistically suppresses E2F-driven transcriptional programs, resulting in robust inhibition of tumor proliferation in both HR+ and TNBC models.In vivo studies using syngeneic and patient-derived xenograft organoid models showed that this combination therapy not only suppresses tumor growth but also reprograms the tumor microenvironment (TME). RNA sequencing of treated tumors revealed upregulation of immune response pathways, including IFN-γ and TNF-α signaling, and increased expression of cytokines such as Cxcl9, Cxcl10, and Ciita. Flow cytometry and immunohistochemistry further confirmed enhanced infiltration of CD8+ T cells and natural killer cells into the TME, accompanied by a reduction in immunosuppressive macrophages. These changes collectively amplify anti-tumor immunity, providing an additional therapeutic benefit.This dual CDK4/6 and CDK7 inhibition approach represents a promising first-line strategy for TNBC and a second-line option for HR+ breast cancer resistant to CDK4/6i and endocrine therapy. These findings not only provide a strong rationale for advancing CDK7i into clinical trials but also highlight the therapeutic potential of targeting transcriptional regulation to overcome resistance in breast cancer. Citation Format: Sungsoo Kim, Eugene Son, Haram Park, Minah Kim, Hee Won Yang. Dual CDK4/6 and CDK7 inhibition: A synergistic strategy to overcome resistance and enhance anti-tumor immunity in breast 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 426.
Abstract 3725: Long-term leisure-time physical activity and digestive system cancer risk and mortality
Authors: Yiwen Zhang, Edward L. Giovannucci
Journal: Cancer Research (2025)

Abstract Introduction: Accumulating evidence indicates physical activity (PA) protects against digestive system cancer (DSC) risk. However, less is clear about its optimal amount, intensity, joint association with sedentary behavior, or its role in DSC mortality. Methods: A total of 231, 067 adults from 3 prospective US cohorts (Health Professionals Follow-up Study, 1988-2020; Nurses’ Health Study [NHS], 1988-2020; NHS II, 1991-2021) were analyzed. Leisure-time PA was assessed biennially via validated questionnaires and expressed in MET-h/week. Time spent sitting watching TV, a widely used surrogate of sedentary behavior, was assessed biennially. DSC encompassed the digestive tract (mouth, throat, esophagus, stomach, small intestine, colon and rectum) and accessory organs (pancreas, gallbladder, and liver). Results: Over up to 32 years of follow-up, we documented 6537 incident DSC and 3789 DSC deaths. Higher PA levels were associated with lower DSC risk (≥45 vs. &amp;lt;3 MET-h/week: HR [95% CI], 0.82 [0.74-0.92]; P-trend&amp;lt;0.001) and mortality (0.72 [0.62-0.84], P-trend&amp;lt;0.001). The inverse association was evident for both digestive tract and digestive accessory organ cancers. The maximum benefit appears to be reached at approximately 50 MET-hours/week for DSC risk (P non-linearity=0.01) and mortality (P non-linearity&amp;lt;0.001). Moderate and vigorous PA was independently associated with lower DSC risk and mortality. Consistently meeting the PA guidelines was further associated with lower risk of DSC. Participants who were highly active and less sedentary had a 22% lower DSC risk (95% CI, 0.69-0.87) than those who were highly sedentary and less active. Conclusion: Higher PA, whether moderate or vigorous, was associated with lower DSC risk and mortality. The optimal benefit was observed at approximately 50 MET-hours/week of total PA. Being consistently physically active may further reduce DSC risk. Increasing PA and reducing sedentariness may be strategies for preventing DSC risk and mortality. Citation Format: Yiwen Zhang, Edward L. Giovannucci. Long-term leisure-time physical activity and digestive system cancer risk and mortality [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 3725.
Abstract 2834: CyclinE1 amplification promotes chromosomal instability and distinct vulnerabilities in gastroesophageal adenocarcinoma
Authors: Zhong Wu, Ankur Nagaraja, Shangwei Sun, Ling Lan, Jin Zhou, Adam Bass
Journal: Cancer Research (2025)

Abstract Background: Gastroesophageal adenocarcinomas (GEA) are characterized by chromosomal instability (CIN) predominantly consisting of high amplitude focal amplifications of oncogenes, including Cyclin E1. An initial pan-cancer analysis revealed that CCNE1 is one of the top genes whose expression correlates with focal CIN. Objective: We proposed a causal role for excess CCNE1 as a driver of CIN and gastroesophageal tumorigenesis, and investigated the therapeutic vulnerabilities of CCNE1 amplification/overexpression. Design: We engineered a novel CCNE1-overexpressing mouse gastric organoid model with Trp53 deletion and studied the functional effects on tumor initiation and progression. Whole genome sequencing of tumors was performed to characterize the effects of CCNE1 overexpression on genomic instability. To identify dependencies of CCNE1-amplified GEA, we executed a CRISPRi functional genomic screen. Top genetic dependencies were translated into potential pharmacologic vulnerabilities and tested in monotherapy and combination. Results: CCNE1 overexpression accelerated tumor initiation and progression of mouse gastric organoids with Trp53 deletion. These tumors demonstrated increased chromosomal complexity, mainly focal amplifications. Our functional genomic screen identified specific genetic dependencies of CCNE1-amplified GEA, including CCNE1/CDK2 as the strongest hits, and SKP2 as a novel dependency likely through its function as a p27 degrader. Pharmacologic inhibition of CDK2 was insufficient and antagonistic with concurrent inhibition of the DNA damage response via targeting the ATR/CHEK1 axis. However, staggered inhibition of these distinct vulnerabilities demonstrated efficacy. Conclusions: Our study identifies CCNE1 as a driver of CIN in GEA and builds a foundation for further exploration of therapies for CCNE1-amplified GEA characterized by genomic instability. Citation Format: Zhong Wu, Ankur Nagaraja, Shangwei Sun, Ling Lan, Jin Zhou, Adam Bass. CyclinE1 amplification promotes chromosomal instability and distinct vulnerabilities in gastroesophageal adenocarcinoma [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 2834.
Abstract 220: Early methylome-level alterations in colorectal adenocarcinoma
Authors: Dalma Muller, Balazs Gyorffy
Journal: Cancer Research (2025)

Abstract Introduction: Methylation-based biomarkers represent a promising tool for early tumor detection in colorectal cancer. Genome-wide methylation analysis of large cohorts is an effective way of for the discovery of new biomarker candidates. For such purposes, Illumina arrays are today the most popular sources of methylation data. Purpose: We aimed to analyze the methylation pattern differences between different groups, especially those involved in normal-adenoma and adenoma-adenocarcinoma transition. In order to enable straightforward exploration of the database we also aimed to establish an interactive web-based platform. Methods: Raw files of 2, 356 samples, out of which 1, 273 were from normal mucosa, 815 from adenocarcinoma, and 258 from precancerous adenoma tissues were processed in R using the minfi and the watermelon libraries. The dataset contains data from both Illumina HumanMethylation450K and EPIC microarray platforms, which were analyzed separately. Based on a matrix of β-values, methylated regions and CpG loci were identified using Kruskal-Wallis-test complemented with ROC analysis. For data visualization we created www.epigenplot.com, a web platform designed for the comprehensive analysis of our database. Results: When compared to normal tissues, the average methylation of both adenoma and adenocarcinoma samples was significantly lower in both HM450K and EPIC arrays (Kruskal-Wallis, p&amp;lt;0.001). The majority of the significant (Δβ &amp;gt;= 0.2, p &amp;lt; 0.001) methylation changes discovered in adenocarcinomas were already detectable in adenoma tissues. This occurred more often for hyper- than hypomethylation (HM450K: 80.5% and 78.58%; EPIC: 79% and 41%, respectively). Out of 75 genes previously proposed in the literature as CRC biomarker candidates, 49 and 45 (HM450K and EPIC) were significantly differentially methylated in adenocarcinoma tissues. Notably, for all these genes, the change was already present in adenoma tissues. When the difference between normal and adenocarcinoma tissues was analyzed, the methylation of the first exon of the C1orf70 gene reached the highest AUC 0.98 at both platforms. For this region, the AUC for normal and adenoma tissues was 0.97 in HM450K and 0.99 in the EPIC dataset. Conclusions: Alternations of the methylome are early events of tumorigenesis. The changes detected by methylation-based biomarkers are already present in precancerous lesions. Our web tool can be utilized for the discovery and validation of biomarkers suitable the early detection of CRC using genome-wide data. Citation Format: Dalma Muller, Balazs Gyorffy. Early methylome-level alterations in colorectal adenocarcinoma [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 220.
Abstract 2716: Role for KMT2C mutation in endometrial cancer pathogenesis
Authors: Juveria Ali, Swornalata Pukhrambam, Sophia Agrusa, Areebah Qazi, Jessica Back, Greg Dyson, Michele L. Cote, Anna Gottschlich, Mike R. Wilson
Journal: Cancer Research (2025)

Abstract Background: Endometrial cancer (EC) is the 4th most common cancer to be diagnosed in women. Although EC has reasonable survival rates, there is a disparity gap for African American (AA) women, as they are twice as likely to succumb to metastatic EC. They are also more likely to develop the more severe subtype, uterine serous carcinoma (USC), and high-grade EC. HER2-positive USC can be treated with Trastuzumab, but response varies. The KMT2C gene encodes a lysine methyltransferase involved in histone modification and transcriptional coactivation. Through a meta-analysis of multiple datasets, we identified KMT2C as highly mutated in High Grade Serous Endometrial Cancer (HGSEC) tumors from AA patients when compared to Non-Hispanic White patients. KMT2C was the top gene mutated when comparing differential mutation rates from this data. Methods: To explore the relationship between KMT2C and EC, we transfected 12Z endometrial epithelial cells with KMT2C siRNA to induce transient knockdown and performed western blots with the transfected protein lysates. Additionally, we transfected cells with plasmids containing green fluorescent protein (GFP), Cas9, and 3 different guide RNAs targeting KMT2C to generate stable knockouts. Flow cytometry isolated the GFP+ cells. Using those isolated 12Z CRISPRCas9 knockouts, we performed a final western blot. Results: KMT2C knockdown led to decreased HER2 expression. KMT2C knockdown increased Arid1a expression and minimally increased Snail and Slug expression. GFP expression confirmed successful transfection. CRISPR KMT2C guide 1 silenced some isoforms of KMT2C. Conclusion: Patients who have KMT2C mutations would likely be less responsive to Trastuzumab due to reduced expression of HER2. Arid1a is mutated in about 10% of human cancers and Snail and Slug are markers of epithelial to mesenchymal transition (EMT), so their overexpression in the KMT2C knockdown may have serious implications. More testing should be done related to EC patients with KMT2C mutations and alternate treatment plans need to be explored for this vulnerable subpopulation. Citation Format: Juveria Ali, Swornalata Pukhrambam, Sophia Agrusa, Areebah Qazi, Jessica Back, Greg Dyson, Michele L. Cote, Anna Gottschlich, Mike R. Wilson. Role for KMT2C mutation in endometrial cancer pathogenesis [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 2716.
Abstract 388: HZ-V068, an oral, highly potent pan-Ras molecular glue inhibitor demonstrated robust potency in pancreatic ductal adenocarcinoma and colorectal cancer models
Authors: Yizhe Wu, Jiangfeng Xie, Jinglai Huang, Xinglu Zhou
Journal: Cancer Research (2025)

Abstract Introduction: Ras oncogenes are frequently mutated in approximately 30% of all human cancers, which drive tumor growth and metastasis. The current approved Kras-targeted drugs are Kras G12C inhibitors. However, Kras G12C is only prevalent in part of lung cancer. Most of common mutations in pancreatic ductal adenocarcinoma (PDAC) or colorectal cancers (CRC) including Kras G12D, G12V, G12R are still lack of approved drugs. RMC6236, a next generation of novel pan-RasMulti(on) inhibitor which functions as molecular glue to form binary complex with CYPA and RasMulti and sterically blocks Ras binding to effectors, has been validated as a superior strategy targeting Ras in clinical study. Given GTP-bound RAS proteins as a promising new approach to enhance clinical benefits, we have developed a novel oral available pan-Ras molecular glue——HZ-V068 based on in-house Rational Molecular Glue Design Platform, which exhibits significantly binding affinity to CYPA, enriched tumor exposure and prolonged Ras inhibition. HZ-V068 has been validated as a promising pre-clinical candidate for further clinical development. Results: 1. In biochemical assays, HZ-V068 more potently disrupted the binding of KRASMut(On) to BRAF in a CypA-dependent manner. 2. HZ-V068 suppressed the growth of KrasMulti-BaF3 cell-line covering various mutation types (G12C/D/V/R, G13C/D, Q61K, A146V) at picomolar level. Moreover, HZ-V068 demonstrated 5-10 folds stronger potency in KrasMulti-addicted cancer cell lines compared to RMC-6236. 3. In a single-dose PK/PD study, HZ-V068 demonstrated rapid and more sustained intratumoral pERK inhibition, improved bioavailability, and enhanced tumor distribution. 4. In multiple KrasMulti-driven PDAC or CRC CDX models, oral administration of HZ-V068 results in robust tumor regression at lower doses, demonstrating efficacy that is significantly superior to that of RMC6236 Conclusion: In summary, HZ-V068 is a promising targeted therapeutic option for PDAC and CRC. Based on these promising results, we are advancing HZ-V068 into clinical study. Citation Format: Yizhe Wu, Jiangfeng Xie, Jinglai Huang, Xinglu Zhou. HZ-V068, an oral, highly potent pan-Ras molecular glue inhibitor demonstrated robust potency in pancreatic ductal adenocarcinoma and colorectal cancer 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 388.
Abstract 907: Identification of a stem cell-specific secretory immune regulatory ligand
Authors: Benjamin T. Nicholson, Ama Ofori, Jennifer Good, Weijie Guo, Yuxuan Miao
Journal: Cancer Research (2025)

Abstract Immunotherapies have transformed cancer treatment, but subsets of patients experience differential responses. Patients with squamous cell carcinomas (SCCs) in various tissues exhibit a high rate of relapse after their initial response to immunotherapies. Recent research highlighted the critical roles of a group of stem cell-like tumor-initiating cells (TICs) in driving the relapse of both cutaneous (CSCCs) and head and neck (HNSCCs). These TICs exhibit superior resistance to anti-tumor immunity despite their intact antigen presentation. Although TICs are the root cause of SCC relapse, they compose less than 5% of the total tumor cell population. Therefore, their unique immune resistance mechanisms have been largely overlooked. Here, we aim to identify the special immune regulatory mechanisms that are specifically activated in TICs endowing them with stronger immune resistance. By analyzing single-cell RNA-seq data profiling the gene signatures of various tumor populations in CSCCs, we identified cytotoxic T lymphocyte antigen 2a (Ctla2a) was specifically activated in TICs. Ctla2a is characterized as a cysteine peptidase inhibitor and has high homology to the I29 inhibitory domain in the proregion of mouse and human cathepsins. Silencing Ctla2a in SCC cells reduced tumor growth, enhanced CD8+ T cell infiltration, and elevated their antigen-specific cytotoxicity. Importantly, we have found that the conditioned medium collected from SCC cells overexpressing Ctla2a is sufficient to blunt the cytokine production of CD8 T cells, suggesting that Ctla2a proteins are secreted from TICs to modulate T cell immunity. Ongoing aims focus on 1) how the peptidase inhibitor activity of Ctla2a reduces cytotoxic cytokine production in CD8+ T cells and 2) whether the I29 inhibitory domain of human cathepsins is capable of conferring the immune-suppressive activity observed in Ctla2a expressing SCCs. Taken together, these results suggest that TICs can secrete these cathepsin inhibitory peptides to perform moonlighting functions and modulate CD8+ T cell anti-tumor cytotoxicity. This interaction may serve as a target for next-generation immunotherapy that is able to blunt TIC-specific immune resistance. Citation Format: Benjamin T. Nicholson, Ama Ofori, Jennifer Good, Weijie Guo, Yuxuan Miao. Identification of a stem cell-specific secretory immune regulatory ligand [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 907.
Abstract 2449: Using digital pathology to differentiate survival phenotypes in high-grade serous ovarian cancer
Authors: Kelsey C. Goon, Leonhard Donle, Ernst Lengyel
Journal: Cancer Research (2025)

Abstract Background: High-grade serous ovarian cancer (HGSOC) has a median survival &amp;lt; 5 years. Yet approximately 10% of patients become long-term survivors (LTS), living &amp;gt; 10 years. Predicting extremes of survival may reveal insights into HGSOC biology. Machine learning (ML) can predict survival outcome in other malignancies from hematoxylin and eosin (H&amp;E) whole slide images (WSIs) though no published models address overall survival (OS) in HGSOC. This project uses ML to predict OS in HGSOC H&amp;E WSIs, comparing tumor and stromal regions. Methods: Short-term survivors (STS) were defined as OS &amp;lt; 2 years and LTS as OS &amp;gt; 7 years. The model was trained on 138 H&amp;E WSIs (56 LTS, 82 STS) at 20x magnification with 5-fold cross-validation repeated 3x and validated on The Cancer Genome Atlas-Ovary (TCGA) dataset (34 WSIs; 6 LTS, 28 STS). After converting WSIs to tiles, features were extracted using the UNI foundation model. A linear discriminant analysis predicted tile association with survival, a pretrained tumor segmentation model separated tumor and stroma, and a logistic regression classifier predicted survival based on the ratio of STS to LTS. Performance was compared across regions: whole slide, tumor alone, stroma alone, a 500-µm band at the tumor-stroma interface, and a combination of tumor-based and stroma-based predictions. Conclusions: Models using both stroma and tumor outperformed compartmentalized models. This trend was consistent in the TCGA dataset though performance dropped significantly, proving the feasibility of using ML on H&amp;E WSIs to predict survival in HGSOC. Our results identify a need to optimize generalizability for this relatively data-scarce malignancy and suggest that successful prediction of OS should acknowledge tumor-stromal interactions. Citation Format: Kelsey C. Goon, Leonhard Donle, Ernst Lengyel. Using digital pathology to differentiate survival phenotypes in high-grade serous 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 2449.