tbuckley/cabot-search huggingface dataset:
Abstract 348: Development of an anti-TF ADC with a potentially improved therapeutic index
Authors: Xiaodong Xiao, Zhidi Pan, Zhangyi Song, Haiyang Yin, Hua Jiang, Yueqing Xie, Jianwei Zhu
Journal: Cancer Research (2025)

Abstract Tissue factor (TF) plays important roles in the hemostasis process. Through forming complex with factor (F) VII/VIIa, TF helps to initiate the blood coagulation process that protects vital organs from excessive bleeding. Under pathological conditions TF could also be involved in thrombosis. Furthermore, TF has functions beyond hemostasis such as signaling. TF is involved in many aspects of cancer transformation such as aberrant signaling, metastasis, and tumor angiogenesis. TF has been found to overexpress in multiple cancers including cervical, pancreatic, lung, head and neck, and prostate cancers, etc. Therapeutics targeting TF has achieved success with most notably the recent approval of Tisotumab Vedotin against cervical cancer. We report here the early phase development of an anti-TF ADC. Our in-house phage display library was employed to isolate a panel of fully human anti-TF antibodies. They vary in binding epitope and affinity allowing the opportunity to evaluate the optimum combination of both to achieve superior efficacy and safety. We found that the binding epitope plays a significant role in the antibody-mediated internalization, whereas within the same binding bin, antibody affinity and internalization may not have a direct correlation. One such antibody, 1E11, has a similar epitope to Tisotumab. It has a modest binding affinity (KD=68 nM) compared to other internal candidates as well as Tisotumab, yet it displayed similar or superior internalization efficiency and ADC mediated cell killing against multiple TF positive cell lines in vitro. In several CDX in vivo models tested so far, 1E11 based ADC showed comparable or superior activities to Tisotumab carrying the same linker/payload. Significantly, while Tisotumab displayed significant disruption of TF/factor VII interaction, a potential cause for excessive bleeding observed in clinics using Tisotumab Vedotin, 1E11 showed little or no such activities. These highly relevant function and safety features of 1E11-based ADC plus its excellent developability profile suggest that it is a promising candidate for further development into various ADC based therapeutics either used alone or in combination with other therapeutics. Citation Format: Xiaodong Xiao, Zhidi Pan, Zhangyi Song, Haiyang Yin, Hua Jiang, Yueqing Xie, Jianwei Zhu. Development of an anti-TF ADC with a potentially improved therapeutic index [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 348.
Abstract 210: Direct multiomic mapping of chromatin proteins and DNA methylation
Authors: Jen Spengler, Bryan J. Venters, Vishnu U. Sunitha Kumary, Allison Hickman, Anup Vaidya, Jonathan M. Burg, Louise Williams, Louise Williams, Chaithanya Ponnaluri, Pierre-Olivier Esteve, Issac Meek, Sriharsa Pradhan, Zu-Wen Sun, Martis W. Cowles, Michael-Christopher Keogh
Journal: Cancer Research (2025)

DNA methylation (DNAme) is a class of epigenetic marks that includes the methylation of cytosine residues (5mC) within CpG islands. In addition to well characterized roles regulating gene expression, imprinting, and silencing parasitic DNA elements, misregulation of DNAme is implicated in multiple cancers. Evidence is emerging that DNAme is not an independent epigenetic mark but rather closely linked to chromatin proteins. However, examining the relationships between DNAme and chromatin proteins is hampered by correlative analyses that cannot establish a direct mechanistic link. Furthermore, the traditional approach to measure DNAme relies upon harsh bisulfite chemical conversion, which introduces DNA breaks and systemic biases. To address these limitations, we developed CUT&amp;RUN-EM: an ultra-sensitive multiomic technology that integrates EpiCypher's CUT&amp;RUN genomic mapping with New England Biolab’s Enzymatic Methyl-seq (EM-seq). Together, these technologies permit high-resolution, simultaneous profiling of chromatin proteins and DNAme, enabling direct interrogation of the complex molecular crosstalk between these genomic features. To quantify the capabilities and limitations of the assay, we tested CUT&amp;RUN-EM across chromatin proteins and cell lines. We show that CUT&amp;RUN-EM is highly reproducible, specific, sensitive, and efficient, requiring as few as 5 million short-read sequences per reaction (10-100x less than whole-genome DNAme sequencing). The advent of CUT&amp;RUN-EM will enable detailed interrogation of the cancer epigenome, providing insights into new therapeutic targets. Citation Format: Jen Spengler, Bryan J. Venters, Vishnu U. Sunitha Kumary, Allison Hickman, Anup Vaidya, Jonathan M. Burg, Louise Williams, Louise Williams, Chaithanya Ponnaluri, Pierre-Olivier Esteve, Issac Meek, Sriharsa Pradhan, Zu-Wen Sun, Martis W. Cowles, Michael-Christopher Keogh. Direct multiomic mapping of chromatin proteins and DNA methylation [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 210.
Abstract 317: Discovery of HDM2017, a CDH17-targeting ADC for colorectal cancers
Authors: Chen Lin, Yan Xia, Liubin Guo, Yang Chen, Tingyang Wang, Kuan Lu, Hao Pan, Yayun Zhao, Jie Fang, Hongwen Li, Dongzhou Jeffery Liu
Journal: Cancer Research (2025)

Abstract Introduction: Cadherin 17 (CDH17) is a cell-to-cell adhesion protein that is a member of the cadherin superfamily. CDH17 is frequently overexpressed in colorectal cancer (CRC), gastric cancer (GC) and pancreas cancer (PC)1. HDM2017 ADC comprises a human monoclonal antibody specifically targeting CDH17 and chemically conjugated to CPT-derivative payloads. HDM2017 is undergoing IND-enabling studies. Methods: In vitro and in vivo preclinical studies were conducted in the discovery of HDM2017 against gastrointestinal cancers. Initial investigations on plasma stability were performed. Exploratory toxicity assessments were carried out in cynomolgus monkeys and rats. Results: HDM2017 demonstrates excellent cell binding activities with CRC and GC cells, with an EC50 ranging between 0.1-1.0nM. Additionally, HDM2017 exhibits strong target-mediated internalization activities, achieving an internalization efficiency of 43-75%. The HDM2017 ADC displays potent expression-dependent in vitro anti-tumor activity in a range of CDH17 expressing tumor cell lines. Treatment with HDM2017 ADC resulted in significant inhibition of tumor growth in xenograft models of CDH17+ human CRC (71∼97% TGI) and GC (71∼90% TGI). HDM2017 ADC exhibited excellent stability in human, monkey, and rat plasma with a drug shedding rate below 0.5%. Toxicity studies primarily revealed payload-related toxicity profile, which supports further development of the ADC molecule. Analysis using CDH17 IHC assay on patient tissues showed detectable expression of CDH17 in 90% (29/29) cases of colorectal cancer, 70% (7/10) cases of gastric cancer and 65% (13/20) cases of pancreas cancer. Conclusion: HDM2017ADC exhibited potent cytotoxicity in vitro and in vivo anti-tumor activity in various gastrointestinal cancer models. The preclinical activity and safety profile warrants further clinical development with biomarker strategy. Overall, the preclinical data presented here suggests that HDM2017 ADC has the potential to provide clinical benefit to gastrointestinal cancer patients. Citation Format: Chen Lin, Yan Xia, Liubin Guo, Yang Chen, Tingyang Wang, Kuan Lu, Hao Pan, Yayun Zhao, Jie Fang, Hongwen Li, Dongzhou Jeffery Liu. Discovery of HDM2017, a CDH17-targeting ADC for colorectal 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 317.
Abstract 3298: LRP12 promotes triple-negative breast cancer metastasis via recruiting the activation of β-catenin and PI3K/AKT signaling pathways
Authors: Kung-Ju Chen, Yuan-Feng Lin
Journal: Cancer Research (2025)

Abstract Background: Triple-negative breast cancer (TNBC) metastasis is the major cause of failure in TNBC therapy. The challenges in treating TNBC may stem from their heightened cellular plasticity, and characterized by significant heterogeneity at the molecular level. As a result, understanding the molecular mechanism for TNBC metastasis is urgently needed for the precise management of TNBC clinically. Low-density lipoprotein receptor-related proteins (LRPs) are the multifunctional transmembrane proteins involved in receptor endocytosis and signal transduction and associated with tumor progression. The aim of this study was made to delineate the role of LRP12 in the metastatic progression of TNBC. Methods: The transcriptional profile of normal tissues and primary tumors derived from TNBC patients obtained from The Cancer Genome Atlas (TCGA) database was used to examine the expression of LRPs. Kaplan-Meier analysis was performed to estimate the prognostic significance of LPRs. Trans-well migration and lung colony-forming assays were established to evaluate the metastatic potentials of TNBC cell variants. RNA-sequencing was employed to generate differentially expressed genes (DEGs) followed by the prediction of possibly activated pathways by pathway enrichment analysis after LRP12 knockdown in the tested TNBC cells. Cycloheximide-chased assay was used to measure the degradation of β-catenin in response to LRP12 knockdown in TNBC cells. Results: Transcriptional profiling and Kaplan-Meier analysis demonstrated that LRP12 upregulation is commonly found in primary tumors compared the normal adjacent tissues and highly associates with the poor prognosis in TNBC patients. LRP12 knockdown predominantly suppressed the cellular migration and lung colony-forming abilities. Pathway enrichment analysis against DEG result from RNA-sequencing indicated that LRP12 knockdown dramatically suppresses the activity of β-catenin and PI3K/AKT signaling pathways in Hs578T cells. Western blot analysis conformed that LRP12 knockdown predominantly reduced the phosphorylated/active β-catenin and PI3K/AKT protein in Hs578T cells. Cycloheximide-chased assay further showed that LRP12 knockdown significantly accelerates the protein degradation of β-catenin in Hs578T cells. Conclusion: These findings highlight the potential role of LRP12 as a prognostic biomarker but also a therapeutic target in metastatic TNBC. Citation Format: Kung-Ju Chen, Yuan-Feng Lin. LRP12 promotes triple-negative breast cancer metastasis via recruiting the activation of β-catenin and PI3K/AKT signaling pathways [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 3298.
Abstract 2098: Development and testing of specimen-protecting microscopy consumables that enable the automation of cyclic immunofluorescence methodology
Authors: Michael Craft, Noemi Kedei, Nels Wedin, Geoffrey K. Feld, Nikolay Samusik
Journal: Cancer Research (2025)

Abstract Introduction: Spatial biology provides unparalleled proteomic and transcriptomic information on the organization of the tumor microenvironment. However, the manual handling and processing of microscope slides hinder the clinical impact of cutting-edge techniques. Experiment and Data: We introduce and test “image-ready” coverpads to automate sample preparation workflows for multiplex immunofluorescence and immunohistochemistry methods on the Parhelia Spatial Station™ system to acquire single cell level spatial information on whole sides. These “permanent” coverpads with 0.07 mm spacers and thickness No. 1.5 simultaneously provide a reaction chamber for capillary-gap application of staining and washing reagents while protecting specimens from damage generally occurring during manual handling, and allow for imaging without the need for coverslip exchange. Image-ready coverpads were applied to different cyclic immunofluorescence (CycIF) assays using automation on the robot, whereby reagents (multiple antibodies or reporters) are cyclically applied, imaged, stripped, and re-applied to build a larger multiplex target panel. The final step in each cycle of these methods is to immerse the specimen in mounting medium and apply coverslip for imaging. Image-ready coverpads combined with Parhelia’s mounting medium that is fluid enough to be applied by the Spatial Station, allowed multi-cycle imaging on multiple microscopes/scanners (Zeiss Axioscanner, Phenocycler Fusion using adapted settings) without fading and tissue damage, and also saving significant amount of time by not having to remove coverslips. These experiments demonstrate the coverpad utility in efficient and consistent antibody staining in cyclic methods. Ongoing studies with assay manufacturers and academic collaborators will further extend and optimize automated protocols to other assays, expanding the utility of these coverpads to a menu of technologies. Conclusion: Overall, Image Ready coverpads provide a facile mechanism enabling the standardization of cyclic immunofluorescence and immunohistochemistry techniques, an essential milestone in translating spatial biology from research to clinical settings. Citation Format: Michael Craft, Noemi Kedei, Nels Wedin, Geoffrey K. Feld, Nikolay Samusik. Development and testing of specimen-protecting microscopy consumables that enable the automation of cyclic immunofluorescence methodology [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 2098.
Abstract 1018: Genetic landscape and functional exploration of kidney cancer predisposition in cross-ancestral populations
Authors: Hongji Dai, Xinlei Chu, Han Du, Shutong Yang, Yanxin Yao, Xinru Yu, Yanrui Zhao, Zhangyan Lyu, Wei Wang, Chao Sheng, Hong Zheng, Fangfang Song, Fengju Song, Mulin Jun Li, Kexin Chen
Journal: Cancer Research (2025)

Abstract The genetic architecture of renal cell carcinoma (RCC) has not been fully characterized, particularly in Asian populations. Here, we conducted a genome-wide association study (GWAS) of 4, 692 RCC patients and 10, 116 controls of Chinese ancestry, extending to a multi-ancestry cohort totaling 879, 498 participants. Our approach unveiled 10 novel RCC-associated loci and a Chinese-specific locus at 12p13.33 with genome-wide significance. Utilizing GWAS results and cross-ancestry expression quantitative trait loci (eQTLs), we achieved a refined identification of RCC-related candidate causal variants and genes. These findings were substantiated through CRISPR-based screenings and multiplexed single-cell perturbations. Functionally, we established a novel association between rs28684409 and the oncogene RPL4 at the complex genetic locus 15q22.31. This top-down genetic study of RCC underscores the utility of integrating cross-ancestry GWASs, QTLs, and functional screens to deeply elucidate complex diseases and identify potential therapeutic targets. Citation Format: Hongji Dai, Xinlei Chu, Han Du, Shutong Yang, Yanxin Yao, Xinru Yu, Yanrui Zhao, Zhangyan Lyu, Wei Wang, Chao Sheng, Hong Zheng, Fangfang Song, Fengju Song, Mulin Jun Li, Kexin Chen. Genetic landscape and functional exploration of kidney cancer predisposition in cross-ancestral populations [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 1018.
Abstract 434: Synergistic suppression of gemcitabine resistance in PDAC by targeting STAT3 and ABCB11
Authors: Tai-Lin Chen, Chi-Wei Chen
Journal: Cancer Research (2025)

Abstract Gemcitabine resistance is a critical challenge in treating pancreatic ductal adenocarcinoma (PDAC). STAT3 is implicated in tumor progression and chemotherapy resistance. This study investigates the role of STAT3 in gemcitabine-resistant PDAC and evaluates the potential of a STAT3 inhibitor (napabucasin) to enhance gemcitabine efficacy. Gemcitabine-resistant PDAC cells were developed via long-term in vitro culture and in vivo xenograft models. The expression of STAT3 and its phosphorylated form (p-STAT3) was analyzed in resistant cells. Cytotoxicity assays evaluated the sensitivity of resistant and non-resistant PDAC cells to gemcitabine, napabucasin, and an EGFR inhibitor (gefitinib). RNA sequencing revealed upregulation of ABCB11, correlating with p-STAT3 levels, suggesting STAT3-driven multidrug resistance. Combination therapies were assessed in vitro using colony formation assays and in vivo using a PDAC xenograft mouse model treated with gemcitabine, napabucasin, and/or the ABCB11 inhibitor glibenclamide. Gemcitabine-resistant PDAC cells (BxPC3-GR and BxPC3-T1-GR) exhibited elevated STAT3 and p-STAT3 levels. Cytotoxicity assays demonstrated resistance to gemcitabine and gefitinib but increased sensitivity to napabucasin. Combination treatment with gemcitabine and napabucasin significantly suppressed colony formation in vitro. In vivo, combining gemcitabine with napabucasin and glibenclamide led to significant tumor growth inhibition in gemcitabine-resistant PDAC xenografts. The combination of gemcitabine, napabucasin, and glibenclamide synergistically suppresses tumor growth in resistant models, highlighting a potential therapeutic strategy to overcome gemcitabine resistance. Further studies are warranted to optimize combination therapies for clinical application. Citation Format: Tai-Lin Chen, Chi-Wei Chen. Synergistic suppression of gemcitabine resistance in PDAC by targeting STAT3 and ABCB11. [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 434.
Abstract 1102: Integrated (epi)genomic atlas for identification of biomarkers in pediatric gliomas
Authors: Devishi Kesar, Michaela Kristina Keck, Robert J. Autry, David T. Jones
Journal: Cancer Research (2025)

Abstract Pediatric gliomas are a heterogeneous group of brain tumors that affect children and adolescents. Despite recent advances in understanding the genetic and molecular underpinnings of these tumors, the precise mechanisms driving their pathogenesis remain elusive. Thus, we comprehensively investigated the regulatory landscape of pediatric gliomas, focusing on the identification of super enhancer regions and novel transcription factors implicated in the development and progression of both low and high grade gliomas. Using chromatin immunoprecipitation sequencing (ChIP-Seq) data we identified super-enhancer regions, which are key regulators of gene expression and to potentially identify novel enhancer hijacking events that have been shown to be important in oncogenic signaling. By leveraging a large dataset of pediatric gliomas omics data, we systematically identified how these super enhancer regions are associated with specific glioma subtypes. Furthermore, to gain a comprehensive understanding of the molecular landscape of pediatric gliomas, integrating ChIP-Seq data with multi-omic datasets, including RNA-Seq and copy number alterations, revealed key driver genes and pathways. This integrative approach allowed us to uncover potential driver genes and signaling pathways associated with pediatric gliomas. These findings offer a comprehensive view of the regulatory mechanisms in pediatric gliomas, highlighting potential biomarkers and therapeutic targets for personalized treatment approaches. Citation Format: Devishi Kesar, Michaela Kristina Keck, Robert J. Autry, David T. Jones. Integrated (epi)genomic atlas for identification of biomarkers in pediatric gliomas [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 1102.
Abstract 3331: Genomic landscape and prognostic indicators in Taiwanese high-grade glioma
Authors: Chun-Yu Liu, Ji-Lin Chen, Chun-Fu Lin, Jui-To Wang, Wei-Hsin Wang, Cheng-chia Lee, Hsin-Hung Chen, Yi-Wei Chen, Shih-Chieh Lin, Chih-Chun Wu, Chi-Cheng Huang, Sanford P. C. Hsu
Journal: Cancer Research (2025)

Abstract Purpose: High-grade gliomas, including glioblastoma (GBM), are characterized by aggressive phenotypes and a high recurrence rate. Molecular subtyping within high-grade gliomas has advanced diagnostic precision and opened pathways for personalized medicine. IDH mutation status, a critical determinant of high-grade glioma subtypes, reflects distinct patterns in genetic profiles and treatment responses. Given the poor prognosis of high-grade gliomas, there is an urgent need for developing diagnostic tools and therapeutic strategies. Experimental Design: In this VGHTPE cohort, we recruited 192 patients diagnosed with high-grade glioma/GBM between 2009 and 2024. Tumor samples were collected for genomic DNA extraction and analyzed using the FoundationOne CDx test. We assessed the association between genomic alterations and clinical outcomes. Results: Tumor samples from 192 patients (ages 4-82) included 134 IDH-wildtype glioblastomas (69.8%) and 58 IDH-mutant high-grade gliomas (30.2%) based on IDH1/2 status. In the VGHTPE cohort, 21 genes displayed genomic alterations in at least 5% of cases. Over 50% of IDH-wildtype glioblastoma patients exhibited TERT promoter or CDKN2A/B mutations, while over 50% of IDH-mutant glioma patients had TP53 and ATRX mutations. Notably, genes predominantly altered in recurrent tissues were linked to Rap1 signaling. Our analysis showed that IDH1 mutations co-occurred with ATRX and CIC alterations but were mutually exclusive with CDKN2A/B, EGFR, MTAP, and PTEN alterations. Alterations in CDKN2A/B, MTAP, EGFR, PTEN, PIK3CA, and KIT were associated with unfavorable outcomes, whereas patients with IDH1, ATRX, and CIC alterations demonstrated better progression-free survival. Conclusion: This study provides a comprehensive genomic profile of Taiwanese patients with high-grade glioma or GBM, supporting the identification of potential prognostic biomarkers. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Chun-Fu Lin, Jui-To Wang, Wei-Hsin Wang, Cheng-chia Lee, Hsin-Hung Chen, Yi-Wei Chen, Shih-Chieh Lin, Chih-Chun Wu, Chi-Cheng Huang, Sanford P. C. Hsu. Genomic landscape and prognostic indicators in Taiwanese high-grade glioma [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 3331.