tbuckley/cabot-search huggingface dataset:
Abstract 1419: RCZY-711, a novel, highly potent, and orally bioavailable menin-MLL inhibitor with superior efficacy in preclinical acute leukemia models
Authors: Chen Celia X.-J., Zhengyong Wan, Yu Bai, Xiaohong Liu, Jianming Bao
Journal: Cancer Research (2025)

Abstract Menin, encoded by the MEN1 gene, is a scaffold protein widely expressed in human tissues, regulating diverse functions through interactions in key signaling pathways. The menin-MLL1 (KMT2A) complex plays a critical role in acute leukemias with KMT2A rearrangements or NPM1 mutations, driving aberrant expression of HOX genes and MEIS1, which promote leukemia development. MLL is a histone H3K4 methyltransferase essential for transcription in embryonic development and hematopoiesis and frequently forms oncogenic fusion proteins via chromosomal translocations. Disrupting the menin-MLL interaction is an effective therapeutic strategy for MLL-rearranged and NPM1-mutant leukemias. The FDA-approved menin inhibitor SNDX-5613 treats relapsed/refractory acute leukemia with MLL translocations, while ongoing trials explore its use in KRAS-mutant solid tumors and Wnt-driven cancers. Another menin inhibitor, KO-539, is being tested in advanced gastrointestinal stromal tumors. Developing novel menin inhibitors with enhanced safety and efficacy remains a significant clinical priority. Herein, we report RCZY-711, a novel, highly potent, and orally bioavailable menin inhibitor with subnanomolar binding affinity, as demonstrated by SPR. Its potency in disrupting the menin-MLL interaction was further validated using a fluorescence polarization assay (subnanomolar IC50). RCZY-711 displayed potent growth inhibition (single-digit nanomolar IC50) in cancer cell lines with KMT2A rearrangements or NPM1 mutations, without cytotoxicity in wild-type MLL cell lines. The compound demonstrated desirable drug-like in vitro ADME characteristics, clean in vitro safety characteristics (hERG IC50 &amp;gt; 20 µM), and excellent pharmacokinetic characteristics across multiple preclinical species. Oral treatment with RCZY-711 also showed strong in vivo anti-tumor efficacy in acute myeloid leukemia xenograft mouse models, including the MV-4-11 xenograft model with the MLL-AF4 fusion. The observed superior in vivo efficacy may be attributed to its high cellular potency and improved half-life (mouse: T1/2 = 2.0 h). In conclusion, RCZY-711 is a novel, highly potent and orally bioavailable menin-MLL inhibitor with best-in-class clinical potential for treating MLL-rearranged and NPM1-mutant acute leukemias. Citation Format: Celia X.-J. Chen, Zhengyong Wan, Yu Bai, Xiaohong Liu, Jianming Bao. RCZY-711, a novel, highly potent, and orally bioavailable menin-MLL inhibitor with superior efficacy in preclinical acute leukemia 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 1419.
Morphogenesis, starvation, and light responses in a mushroom-forming fungus revealed by long-read sequencing and extensive expression profiling
Authors: Botond Hegedüs, Neha Sahu, Balázs Bálint, Sajeet Haridas, Viktória Bense, Zsolt Merényi, Máté Virágh, Hongli Wu, Xiao-Bin Liu, Robert Riley, Anna Lipzen, Maxim Koriabine, Emily Savage, Jie Guo, Kerrie Barry, Vivian Ng, Péter Urbán, Attila Gyenesei, Michael Freitag, Igor V Grigoriev, László G Nagy
Journal: Cell Genomics (2025)

Mushroom-forming fungi (Agaricomycetes) are emerging as pivotal players in several fields of science and industry. Genomic data for Agaricomycetes are accumulating rapidly; however, this is not paralleled by improvements of gene annotations, which leave gene function notoriously poorly understood. We set out to improve our functional understanding of the model mushroom Coprinopsis cinerea by integrating a new, chromosome-level assembly, high-quality gene predictions, and functional information derived from broad gene-expression profiling data. The new annotation includes 5' and 3' untranslated regions (UTRs), polyadenylation sites (PASs), upstream open reading frames (uORFs), splicing isoforms, and microexons, as well as core gene sets corresponding to carbon starvation, light response, and hyphal differentiation. As a result, the genome of C. cinerea has now become the most comprehensively annotated genome among mushroom-forming fungi, which will contribute to multiple rapidly expanding fields, including research on their life history, light and stress responses, as well as multicellular development.
The interpeduncular nucleus blunts the rewarding effect of nicotine
Authors: Joachim Jehl, Maria Ciscato, Eléonore Vicq, Nicolas Guyon, Gabrielle Dejean de la Batie, Sarah Mondoloni, Jacinthe Frangieh, Monir Mohayyaei, Claire Nguyen, Stéphanie Pons, Uwe Maskos, Jean-Pierre Hardelin, Fabio Marti, Pierre-Jean Corringer, Philippe Faure, Alexandre Mourot
Journal: Neuron (2025)
Abstract 1766: PE-0260, an oral brain-penetrant MTA-cooperative PRMT5 inhibitor, drives tumor regressions in MTAP-deleted solid tumors
Authors: Cheng-Hao Liu, Hui-Ling Chen, Chieh-Fang Cheng, Feng-Yu Lee, Long-Zhi Lin, Hong-Ren Wang
Journal: Cancer Research (2025)

Abstract PE-0260 is a potent and selective oral methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor leveraging the synthetic lethal relationship of PRMT5 with methylthioadenosine phosphorylase (MTAP) gene deletion. The well-studied synthetic lethality is an attractive approach for multiple cancer treatments due to the 10-15% incidence rate of MTAP deletion in all cancers. PE-0260 shows good potency of MTAP del cell viability (&amp;lt;5 nM IC50) and &amp;gt;200X selectivity compared with isogenic MTAP WT cells. In a diverse cell line panel, PE-0260 selectively inhibits MTAP del cell lines over MTAP WT cell lines with median IC50 &amp;lt; 30 nM and &amp;gt;50X selectivity across NSCLC, GBM, pancreatic and breast cancers. This outstanding potency was successfully translated to dose-dependent anti-tumor activities observed in xenograft models with tumor regressions, and significant inhibition of symmetric dimethylarginine (SDMA) modified protein formation in tumors. Through the PK-PD analysis, on-target driven efficacy has been demonstrated, suggesting a low likelihood of off-target toxicity. PE-0260 also shows balanced in vitro ADME properties with low risk for drug-drug interactions and the capability to penetrate the blood-brain barrier. In conclusion, PE-0260 is a potential best-in-class MTA-cooperative PRMT5 inhibitor and a strong candidate for further clinical development. Citation Format: Cheng-Hao Liu, Hui-Ling Chen, Chieh-Fang Cheng, Feng-Yu Lee, Long-Zhi Lin, Hong-Ren Wang. PE-0260, an oral brain-penetrant MTA-cooperative PRMT5 inhibitor, drives tumor regressions in MTAP-deleted 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 1766.
Abstract 2161: Improving the tumor microenvironment with liposomal gemcitabine, FF-10832, enhances the effects of immune checkpoint blockade
Authors: Tadaaki Ioroi, Michie Morimoto, Hitomi Nishinakamura, Keisuke Watanabe, Shohei Koyama, Hiroyoshi Nishikawa, Mikinaga Mori, Susumu Shimoyama
Journal: Cancer Research (2025)

Abstract Cancer immunotherapy, including immune checkpoint blockade (ICB), is a type of cancer treatment that achieves tumor regression in various types of cancer. However, more than half of patients are resistant to ICB therapy. As the tumor microenvironment (TME) is different in each cancer patient, it is important to understand the state of immune cells in the tumor and develop strategies, including combination therapies. In the TME, immunosuppressive cells such as regulatory T cells (Treg), tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) work in correlation with ICB resistance. These immunosuppressive cells are promising targets for ameliorating resistance to ICB treatment and a lot of drugs targeting these cells have been developed. In particular, the therapy targeting TAMs have proved effective. We previously developed liposomal nanoparticle, FF-10832, encapsulating the cytotoxic anti-tumor drug, gemcitabine. Non-clinical studies demonstrated that FF-10832 was more stable than unencapsulated gemcitabine and preferentially distributed to solid tumor sites, resulting in an improved therapeutic index. A phase I clinical trial indicated that FF-10832 was well-tolerated in heavily pre-treated patients with advanced solid tumors at the recommended phase 2 dose (NCT03440450). Therefore, this study investigated the application of FF-10832 as an immunomodulator in combination therapy with ICB. Treatment of mouse models of solid tumor and in vitro analysis showed that FF-10832 is engulfed into the cytoplasm of TAMs in the tumor by phagocytosis. Combination therapy with FF-10832 and anti-PD-1 antibody resulted in significant tumor regression compared to gemcitabine monotherapy, altering the balance immunosuppressive cells in the TME. These results suggest that FF-10832 is a promising immunomodulator for TAM-targeted cancer immunotherapy. Combination therapy of FF-10832 and pembrolizumab is under investigation for non-small cell lung cancer and urothelial cancer in a phase 2a clinical trial (NCT05318573). Citation Format: Tadaaki Ioroi, Michie Morimoto, Hitomi Nishinakamura, Keisuke Watanabe, Shohei Koyama, Hiroyoshi Nishikawa, Mikinaga Mori, Susumu Shimoyama. Improving the tumor microenvironment with liposomal gemcitabine, FF-10832, enhances the effects of immune checkpoint blockade [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 2161.
Abstract 217: Analysis of chromatin accessibility profiling reveals epigenetic features of azacitidine response in high-risk myelodysplastic syndrome
Authors: Dayoung Kim, Silvia Park, Yoo Jin Kim, Ryan Corces, Seung Woo Cho
Journal: Cancer Research (2025)

Abstract Azacitidine, a hypomethylating agent, is currently represented as initial therapy in most cases of high-risk myelodysplastic syndromes (MDS), yet only 40-60% of patients achieve therapeutic response. Non-responders face poor outcomes and disease progression to secondary acute myeloid leukemia. To improve treatment outcomes, understanding the pre-treatment molecular determinants of azacitidine response is critical. Despite the fundamental role of epigenetic regulation and cellular composition in MDS, the complex interplay between epigenetic regulation and therapeutic response has not been investigated. Here, we analyzed chromatin accessibility landscapes of 23 high-risk MDS patients before getting azacitidine, using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). We identified 1, 940 distinct chromatin accessibility features strongly associated with azacitidine response, suggesting gene regulatory elements like enhancers as key determinants of it. Also, non-responders exhibited significant myeloid lineage commitment, while responders showed elevated accessibility in regions governing immune activation and T cell differentiation pathways. Notably, T cell subsets of non-responders displayed distinct chromatin states associated with impaired cellular differentiation compared to responders and healthy donors. This study first establishes chromatin accessibility features as potential biomarkers for azacitidine response in high-risk MDS and provides novel insights for personalized treatment optimization. Citation Format: Dayoung Kim, Silvia Park, Yoo Jin Kim, Ryan Corces, Seung Woo Cho. Analysis of chromatin accessibility profiling reveals epigenetic features of azacitidine response in high-risk myelodysplastic syndrome [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 217.
Abstract 3417: Preclinical studies of BR-2302: A HER3xEGFR bi-specific Exd-containing ADC
Authors: Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Qi Zhang, Ziping Wei, Yuhong Zhou
Journal: Cancer Research (2025)

Abstract HER3 has emerged as a critical player in the resistance mechanisms against therapies targeting the epidermal growth factor receptor (EGFR). Its upregulation can activate alternative signaling pathways, enabling cancer cells to bypass the effects of EGFR inhibitors, which often results in treatment failure. To combat this issue, novel HER3-targeting therapies are under investigation, including antibody-drug conjugates (ADCs) such as Patritumab Deruxtecan (U3-1402), which have shown encouraging results in clinical trials, underscoring the potential of HER3 targeting to overcome resistance. The development of bispecific ADCs that target both HER3 and EGFR represents a pioneering approach that may enhance therapeutic efficacy through dual targeting. Izalonatamab brengitecan (BL-B01D1), an ADC designed for simultaneous targeting of EGFR and HER3, has demonstrated substantial clinical benefits in heavily pretreated patients with EGFR-mutant non-small cell lung cancer (NSCLC). Building on this strategy, we are advancing a novel bispecific ADC, BR-2302, which employs a human IgG1 format bi-specific antibody with high affinity for HER3 and moderate affinity for EGFR. This innovative design aims to maximize therapeutic effectiveness while minimizing on-target/off-tumor toxicity associated with the widespread expression of EGFR in normal tissues. Our comprehensive studies on BR-2302 have focused on its in vitro cytotoxicity and in vivo tumor inhibitory effects across various cancer cell lines and xenograft models expressing the target antigens. BR-2302 exhibited significant anti-tumor activity in vitro, achieving subnanomolar IC50 values against HER3-expressing cell lines regardless of their EGFR expression levels. in vivo experiments demonstrated remarkable tumor growth inhibition and sustained regression in human lung and colon cancer xenograft models, surpassing the tumor inhibitory effects of established benchmark ADCs. Collectively, our findings indicate that BR-2302 possesses promising anti-tumor properties. This innovative therapeutic approach has the potential to improve treatment outcomes for patients with solid tumors expressing both HER3 and EGFR, warranting further clinical exploration. Citation Format: Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Qi Zhang, Ziping Wei, Yuhong Zhou. Preclinical studies of BR-2302: A HER3xEGFR bi-specific Exd-containing ADC [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 3417.
TRAIT: A Comprehensive Database for T-cell Receptor–Antigen Interactions
Authors: Mengmeng Wei, Jingcheng Wu, Shengzuo Bai, Yuxuan Zhou, Yichang Chen, Xue Zhang, Wenyi Zhao, Ying Chi, Gang Pan, Feng Zhu, Shuqing Chen, Zhan Zhou
Journal: Genomics Proteomics & Bioinformatics (2025)
Abstract 2012: Prognostic role of CD3+and CD8+cells density in resected stage IIIAN2 non-small cell lung cancer (NSCLC): A study from the randomized Lung ART IFCT 0503 trial
Authors: Víctor Albarrán-Artahona, Maria-Rosa Ghigna, Wael Zrafi, Nicolas Signolle, Guillaume Granier, Nathalie Cozic, Julien Adam, Ludovic Lacroix, Benjamin Besse, Cécile Le Pechoux, Antonin Levy
Journal: Cancer Research (2025)

BACKGROUND: Immune cells (IC) density has a prognostic role in NSCLC1. Most results come from small cohorts with limited representation of stage III samples and show heterogeneity2-4. METHODS: The LungART trial (NCT00410683)5 randomized 501 patients (pts) with resected stage IIIAN2 NSCLC (AJCC 7th ed.) to adjuvant radiotherapy (ART) or observation. Up to 96% had (Neo)adjuvant chemotherapy (ChT). No disease-free survival (DFS) benefit was found for ART. For pts who consented, a primary tumor blocs was collected; CD3+/CD8+ cells were assessed by immunohistochemistry (DAKO/Roche). Automatic quantitative analysis of selected regions of interest was performed using the QuPath v.0.5.1 Bioimage software for assessment of IC density and correlated with outcomes. RESULTS: 272/501 pts had available samples; 47% received ART. Baseline characteristics were well balanced (table 1). A higher CD3+ cells density was found in non-squamous histology (p=0.003) and in pts receiving neoadjuvant ChT (p=0.03). Higher density of CD3 +and CD8 + cells correlated with the incidence of new events after 6 (p=0.0004 and 0.04, respectively) and 24 months (m) (p=0.003 and 0.04 respectively). High CD3 +cells density correlated with longer median DFS: 52 m (95% CI: 26.1 m-NR) vs 22 m (95% CI: 22.5-31.2 m,) as well as high CD8 + cells density (52.1 m; 95% CI: 34-NR vs 20.9 m; 95% CI: 16.9-28.8 m). A multivariate Cox model confirmed both high CD3 +and CD8 + cell density as independent prognostic factors for DFS (HR=0.68 [95%CI: 0.53-0.83], p=0.01 and HR=0.57 [95%CI: 0.38-0.86], p=0.07, respectively) and overall survival (HR=0.66; 95%CI: 0.49-0.88; p=0.005 and HR=0.5; 95%CI: 0,30-0.85; p=0.10, respectively). CONCLUSIONS: Our study is the largest cohort showing a prognostic role of IC density in resected stage IIIAN2 NSCLC, composed solely by surgical samples, which may identify a subset of poor prognosis pts who could benefit of an intensive therapeutic approach. Citation Format: Víctor Albarrán-Artahona, Maria-Rosa Ghigna, Wael Zrafi, Nicolas Signolle, Guillaume Granier, Nathalie Cozic, Julien Adam, Ludovic Lacroix, Benjamin Besse, Cécile Le Pechoux, Antonin Levy. Prognostic role of CD3and CD8cells density in resected stage IIIAN2 non-small cell lung cancer (NSCLC): A study from the randomized Lung ART IFCT 0503 trial [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 2012.
Abstract 1049: Advancing health equity in oncology through AI, GIS, and data-driven tools
Authors: Ahmed Fadiel, Saleh Fadel, W. Butt, K.D. Eichenbaum, M. Abbasi, A. Elbialy, Kunle Odunsi
Journal: Cancer Research (2025)

Abstract Cancer outcomes are influenced by geographic, socioeconomic, and environmental factors, especially in rural and underserved urban areas. Such regions often lack appropriate screening and specialized care, leading to late-stage diagnoses and poor overall outcomes. Key socioeconomic determinants influencing disparities in cancer care include income, education, environmental conditions, insurance status, and geographic proximity to qualified healthcare providers. To address these inequities, sophisticated tools are needed to identify high-risk areas and to improve resource allocation. To address this need, we developed the Intelligent Cancer Catchment Area Tool (iCAT), a GIS-enabled platform enhanced by artificial intelligence (AI). iCAT integrates public health sources and health systems data to generate a comprehensive, geographically diverse analysis of cancer disparities. On this platform, mapping capabilities are analyzed with advanced statistics and machine learning algorithms to derive actionable insights into cancer social and environmental drivers of gaps in healthcare. Two recent module additions to iCAT are 1. integration of authoritative datasets, including SEER, CDC, and other trusted sources, and 2. advanced preprocessing, in which LLMs are used to clean data and handle confounders. We have improved the analytics package to enable univariate and multivariate analyses to find more complex relationships among the variables. We are adding AI-assisted literature matching to help formulate and suggest evidence-based research questions. Future directions for iCAT include quantum-enhanced predictive modeling, real-time analytics with biometric data from wearable devices, and hyper-localized risk assessment using augmented reality visualizations. We also plan to incorporate blockchain for data security and AI-driven optimization algorithms that guarantee privacy while enhancing intervention planning. We are developing iCAT as a tool for healthcare providers, policymakers, and researchers to make evidence-based decisions. With further development, we anticipate use cases ranging from deploying mobile screening units to culturally adapted educational programs and forming policy reforms. This new approach is a key milestone toward eliminating health disparities and redefinition of equitable cancer care." Citation Format: Ahmed Fadiel, Saleh Fadel, W. Butt, K.D. Eichenbaum, M. Abbasi, A. Elbialy, Kunle Odunsi. Advancing health equity in oncology through AI, GIS, and data-driven tools [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 1049.
Prognostic Value of CD8+ T Cells at the Invasive Margin Is Comparable to the Immune Score in Nonmetastatic Colorectal Cancer: A Prospective Multicentric Cohort Study
Authors: Durgesh Wankhede, Niels Halama, Matthias Kloor, Dominic Edelmann, Hermann Brenner, Michael Hoffmeister
Journal: Clinical Cancer Research (2025)

Abstract Purpose: The Immunoscore predicts colorectal cancer prognosis but faces adoption barriers because of complex software and reimbursement issues. This study used open-source methods to explore a simplified prognostic model in nonmetastatic colorectal cancer by focusing on single T-cell markers. Experimental Design: A multicentric prospective cohort study in patients with nonmetastatic colorectal cancer assessed CD3+ and CD8+ tumor-infiltrating lymphocytes (TIL) in the invasive margin (IM) and tumor core (TC) using QuPath. An immune cell score (ICS), based on TIL densities (CD3-IM, CD8-IM, CD3-TC, and CD8-TC), was calculated similarly to the Immunoscore. A split sample approach (70:30) estimated adjusted HRs for cancer-specific survival in training and validation sets. Classification and regression tree analysis identified the most prognostic TIL, and its model was compared with an ICS model for performance (Brier score) and discrimination (concordance probability estimate). Results: Over a median follow-up of 9.0 years, 203 colorectal cancer–specific deaths occurred among 1,260 patients. Classification and regression tree–selected CD8-IM was the most prognostic TIL at a cutoff of 231 cells/mm2. Patients with high CD8-IM had better cancer-specific survival than low CD8-IM in both training (HR 0.58, 95% confidence interval, 0.40–0.84) and validation sets (HR 0.35, 95% confidence interval, 0.21–0.60). Brier scores of CD8-IM and ICS survival models were comparable in both training and validation cohorts, whereas the survival discrimination of CD8-IM slightly outperformed the ICS in the validation set (concordance probability estimate: CD8-IM: 0.748; ICS: 0.730). Conclusions: CD8-IM alone provided prognostic information comparable with the ICS. Simplified, cost-effective TIL assessments could improve clinical translation and guide adjuvant therapy in early-stage colorectal cancer.
Safety and Tolerability of Lete-cel in NSCLC—Reply
Authors: Mehmet Altan, Gilberto Lopes, T. Jeroen N. Hiltermann, Ramaswamy Govindan, Liza C. Villaruz, Emiliano Calvo, Martin J. Edelman, Muhammad Furqan, Joel Neal, Enriqueta Felip, Jennifer W. Carlisle, John V. Heymach, Róisín Eilish O’Cearbhaill, Marjorie Zauderer, Michael Chisamore, Ellie Corigliano, Ioanna Eleftheriadou, Stefan Zajic, Ben Jenkins, Sophia Goodison, Sunil Suchindran, Natalia Ramos-Hernandez, Nidale Tarek, Adam J. Schoenfeld
Journal: Clinical Cancer Research (2025)