tbuckley/cabot-search huggingface dataset:
Abstract 5022: iS3RGs: Discriminating diverse medulloblastoma subtypes by leveraging heterogenous transcriptome data with batch effects
Authors: Mengtao Sun, Jieqiong Wang, Shibiao Wan
Journal: Cancer Research (2025)

Abstract As the most common malignant pediatric brain cancer, medulloblastoma (MB) accounts for around 20% of all pediatric central nervous system (CNS) neoplasms. MB includes a complex array of distinct molecular subtypes characterized by morphological, molecular, and genetic alterations, mainly including SHH, WNT, Group3 and Group4. Although the overall cure rates for MB are around 70%, the survival rate varies significantly across different molecular subtypes. Conventional experimental methods for identifying MB subtypes are usually costly, time-consuming, and labor-intensive. Accurate identification of MB subtypes enables improved downstream risk stratification and tailored therapeutic treatment design. Previous studies indicate that identifying MB subtypes based on transcriptome data is an efficient and feasible way. However, their performance may be poor due to limited cohorts and severe batch effects if combining data in different sequencing platforms and various data sources. To overcome these limitations, we propose a novel computational approach based on intra-sample subtype-specific ranked genes (iS3RGs) analysis to effectively integrate heterogeneous transcriptomic data with batch effects for accurate identification of MB subtypes across diverse cohorts. For a baseline microarray dataset comprising 763 samples as training part, we specifically converted the absolute gene expression to the intra-sample rank values to capture reliable gene patterns by reducing bias from fluctuations and measurement errors. By comparing gene pairs within cohorts rather than across cohorts, we could avoid batch effects and successfully identified those gene pairs that significantly contributed to the identification of MB subtypes. Subsequently, we performed differential ranking analysis for iS3RGs identification. These genes were organized into gene ranking ratios and the subtype-specific gene ratios were filtered using Fisher’s exact test and LASSO regression, based on which 1035 gene ratios (corresponding to 738 unique genes) were identified. Then by testing on 14 independent datasets, our proposed method significantly outperformed state-of-the-art MB subtyping approaches with a median accuracy of 99.02%. We believe that our proposed approach has direct positive impacts on downstream MB risk stratification and tailored treatment design. We also expect that our proposed approach has great potential to address many biomedical problems with batch effects for various types of pediatric, adolescent, and young adult (AYA) cancers. Citation Format: Mengtao Sun, Jieqiong Wang, Shibiao Wan. iS3RGs: Discriminating diverse medulloblastoma subtypes by leveraging heterogenous transcriptome data with batch effects [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 5022.
Abstract 5501: An integrated end-to-end platform facilitating the evaluation of next generation KRAS inhibitors
Authors: Di Zhan, Lingling Huang, Lei Zhang, Ting Ma, Yuzhou Xu, Yinfei Yin, Zichun Wang
Journal: Cancer Research (2025)

Abstract Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene, and has attracted substantial attention in the preclinical arena. Over the last 40 years, KRAS has been deemed a challenging therapeutic target and has even been described as “undruggable” due to the intrinsic characteristics of KRAS proteins. This has resulted in an urgent and unmet clinical need to target KRAS mutations in KRAS-driven cancer. Recent advances have uncovered a new allosteric site of KRAS (G12C) that facilitates the development of novel covalent allosteric inhibitors targeting this shallow pocket on the surface of KRAS, thereby raising the hope of effectively drugging KRAS. Encouraging clinical trial results have been reported for two KRAS G12C inhibitors, AMG510 (sotorasib) and MRTX849 (adagrasib), with AMG510 being approved by the FDA for clinical use in 2021. Despite the clinical benefits of KRAS G12C inhibitors such as AMG510 and MRTX849, there are still problems that need to be overcome including optimization of clinical efficacy and overcoming drug resistance. Recent clinical research has identified diverse genomic and histological features underlying the resistance of KRAS G12C mutant cancer patients. These resistance mechanisms include co-occurring mutations such as KEAP1, SMARCA4 and CDKN2A, and the acquisition of genetic mutations such as H95D, H96D and R68S in the switch-II pockets. Other non-genetic mechanisms such as reactivation of RAF-MEK-ERK pathway and cell state transition have also been identified. To enable discovery of the new generation of KRAS inhibitors, we have developed a comprehensive KRAS assay platform, which includes biochemical and cell based in vitro assays, and in vivo efficacy evaluation in KRAS mutant xenograft models. In addition, to allow researchers to have a better understanding of the biological basis of drug resistance, we have established and validated a panel of lung and pancreatic cell models that are resistant to AMG510 and MRTX849 through CRISPR-Cas9 editing and drug-induced approaches. Our continuously evolving assay platform facilitates the discovery and development of new generation KRAS inhibitors and combinational strategies. Citation Format: Di Zhan, Lingling Huang, Lei Zhang, Ting Ma, Yuzhou Xu, Yinfei Yin, Zichun Wang. An integrated end-to-end platform facilitating the evaluation of next generation KRAS inhibitors [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 5501.
Abstract 3028: Tumor suppressor activation: unlocking a novel path to overcome CDK4/6 inhibitor resistance in HR-positive breast cancer
Authors: Hee-Sung Park, Kyu-Kwang Cho, Martin Pettersson, Chakrapani Subramanyam
Journal: Cancer Research (2025)

Abstract Clinically approved CDK4/6 inhibitor drugs, though initially effective, often generate acquired resistance in HR-positive breast cancer, leading to 25-35% of patients becoming nonresponsive. A number of drivers for this resistance have been identified, including cyclin D1 upregulation. Herein, we present an innovative strategy to tackle this pressing challenge. We have developed a novel small molecule, PMG-A7, that activates a key tumor suppressor critical to maintaining cellular homeostasis and regulating the cell cycle. PMG-A7 induces a robust, dose-dependent reduction in resistance drivers, demonstrating efficacy at single-digit nanomolar concentrations. Further, PMG-A7 upregulates cell cycle inhibitors such as p27, effectively countering CDK4/6 inhibitor resistance. When used in combination with a CDK4/6 inhibitor, PMG-A7 significantly suppresses resistance mechanisms. These findings highlight tumor suppressor activation as a promising combination therapeutic strategy to help overcome drug resistance to CDK 4/6 inhibitors in the clinic. Citation Format: Hee-Sung Park, Kyu-Kwang Cho, Martin Pettersson, Chakrapani Subramanyam. Tumor suppressor activation: unlocking a novel path to overcome CDK4/6 inhibitor resistance in HR-positive 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 3028.
Abstract 4254: Development of DEM201, a blocking antibody against SMAGP, a novel “Don′t Eat Me” signal overexpressed in cancer
Authors: Sarah E. Carden, Agnieszka Denslow, Mary Baumel, Jing Zhu, Lissette Garcia, Sarah Nesti, Kayla Belanger, Meghan Davis, Carmen Adriaens, Sandeep Kumar, Christophe Quéva, Loise Francisco
Journal: Cancer Research (2025)

Abstract Small Cell Adhesion Glycoprotein (SMAGP), a poorly characterized glycoprotein thought to function in cell adhesion, is highly expressed in gastrointestinal (GI) cancers and overexpressed in bladder cancer, hepatocellular carcinoma, kidney papillary cell carcinoma, pancreatic adenocarcinoma, thyroid carcinoma, and endometrial carcinoma. SMAGP was recently identified as a novel “Don’t Eat Me” (DEM) signal, and overexpression of human SMAGP suppresses tumor cell phagocytosis by primary human macrophages. Unlike the canonical DEM signal CD47, SMAGP is not detected in platelets or erythrocytes. Two cellular receptors for SMAGP have been identified, PILRα, an ITIM-containing transmembrane receptor broadly expressed in the myeloid lineage, and CD177, a GPI-anchored neutrophil marker also expressed in some epithelial cells and tumor-associated regulatory T cells (Tregs). To investigate the role of SMAGP in regulating anti-tumor responses, monoclonal antibodies were raised against SMAGP and humanized. DEM201 was selected as a clinical candidate and is specific for human SMAGP with sub-nanomolar (nM) affinity. DEM201 binds cell-associated SMAGP on cancer cell lines derived from GI, pancreatic and lung cancer and elicits potent ADCP and ADCC with sub-nM EC50. In vivo, DEM201 significantly inhibited the growth of SMAGP-expressing RKO tumor xenografts. To assess the potential of SMAGP inhibition in regulating both innate and adaptive immunity in vivo, we tested mAb255-mIgG2a, a SMAGP mAb with sub-nanomolar affinity to mouse SMAGP, in immunocompetent syngeneic tumor models. mAb255-mIgG2a potently inhibited the growth of H22 and Hepa1-6 liver cancer. A significant increase in CD8 T cells and macrophages was observed in H22 tumors after treatment with mAb255-mIgG2a. All SMAGP mAb treatments were well-tolerated, clearing the way for DEM201 IND-enabling activities. Citation Format: Sarah E. Carden, Agnieszka Denslow, Mary Baumel, Jing Zhu, Lissette Garcia, Sarah Nesti, Kayla Belanger, Meghan Davis, Carmen Adriaens, Sandeep Kumar, Christophe Quéva, Loise Francisco. Development of DEM201, a blocking antibody against SMAGP, a novel “Don′t Eat Me” signal overexpressed in 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 4254.
Abstract 5449: Preclinical development of SCR-A003, a novel topoisomerase I inhibitor-based antibody-drug conjugate (ADC) targeting LIV-1 for solid cancer
Authors: Yayuan Fu, Changyan Chen, Xiaohua Yan, Zhiyong Yu, Zhuangzhi Zhao, Jingli Liao, Zhenyun Tian, Renhong Tang
Journal: Cancer Research (2025)

Abstract Background: LIV-1, also known as SLC39A6 or ZIP6, a multi- transmembrane protein with putative zinc transporter and metalloproteinase activity. LIV-1 is expressed in a number of cancers with the highest prevalence in breast, prostate, ovary and melanoma, but a limited presence in vital organs. Currently, the clinical-stage ADC drug targeting LIV-1, Ladiratuzumab vedotin (SGN-LIV1A), is undergoing Phase 2 trials and has demonstrated clinical benefits, thus further underscoring LIV-1 as a promising target for advanced solid tumors. Given the broad spectrum of tumor indications addressable by targeting LIV-1, we utilized Simcere Zaiming’ proprietary ADC technology to generate a novel ADC targeted to LIV-1 named SCR-A003. Method: SCR-A003 is comprised of a LIV-1-targeted monoclonal antibody linked to a novel cytotoxic topoisomerase I inhibitor by a protease-cleavable linker. Pharmacokinetic study was conducted in mice in which SCR-A003 administered IV infusion. In vivo efficacy studies were conducted in immunodeficient mice with human tumor cell-lines including NCI-H838 and OVCAR3.The anti-tumor efficacy of SCR-A003 was evaluated in comparison to SGN-LIV1A analogue. Result: SCR-A003 had highly specific binding affinity with human and could cross-bind to cyno LIV-1. Moreover, SCR-A003 exhibited excellent internalization and cell killing ability on multiple tumor cells in-vitro assay. SCR-A003, demonstrated specific, dose-dependent in vivo antitumor activity toward LIV-1-positive tumor xenografts representing lung, ovary and breast cancers. Compared to SGN-LIV1A analogue, SCR-A003 exhibited more robust tumor inhibition capacity at lower doses in OVCAR3 and NCI-H838 xenograft models. Additionally, SCR-A003 also showed prolonged serum half-life and higher drug exposure than SGN-LIV1A analogue in pharmacokinetic study. Conclusions: SCR-A003, exhibited a favorable preclinical profile, with potent in vivo activity toward LIV-1-expressing tumor xenografts representing a range of cancer indications. These data support clinical development of SCR-A003 for the treatment of LIV-1-expressing solid cancers. Citation Format: Yayuan Fu, Changyan Chen, Xiaohua Yan, Zhiyong Yu, Zhuangzhi Zhao, Jingli Liao, Zhenyun Tian, Renhong Tang. Preclinical development of SCR-A003, a novel topoisomerase I inhibitor-based antibody-drug conjugate (ADC) targeting LIV-1 for solid 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 5449.
Abstract 4167: CK2 inhibition restores IKAROS-mediated metabolic control and induces cell death in acute lymphoblastic leukemia
Authors: Diwakar Bastihalli Tukaramrao, Arati Sharma, Dhimant Desai, Sinisa Dovat
Journal: Cancer Research (2025)

Abstract The transcription factor IKAROS functions as a critical metabolic gatekeeper in B cells by regulating glucose metabolism and the pentose phosphate pathway (PPP). In lymphoid leukemias, casein kinase 2α (CK2α) overexpression impairs IKAROS function, leading to dysregulated cellular metabolism. This study investigated the metabolic consequences of CK2α inhibition in B- and T-cell acute lymphoblastic leukemia (ALL). Treatment of ALL cell lines with the CK2 inhibitor CX4945 resulted in significant cell death, with IC50 values ranging from 4-10 µM. In NALM6 cells, CK2α inhibition led to increased reactive oxygen species (ROS), decreased NADPH/NADP+ ratio, and reduced glucose consumption by 40%. Additionally, CX4945 treatment significantly decreased both glycolytic activity and mitochondrial respiration in ALL cell lines (NALM6, 697, MOLT4 and CEM). Metabolomic analysis revealed 64 differentially expressed metabolites between CX4945-treated and vehicle-treated NALM6 cells, with notable reductions in glycolytic intermediates. These findings demonstrate that CK2α inhibition effectively restores IKAROS-mediated metabolic control, leading to energy deficiency and increased oxidative stress in ALL cells. This work provides evidence that targeting the CK2-IKAROS axis represents a promising therapeutic strategy for ALL through metabolic modulation. Citation Format: Diwakar Bastihalli Tukaramrao, Arati Sharma, Dhimant Desai, Sinisa Dovat. CK2 inhibition restores IKAROS-mediated metabolic control and induces cell death in acute lymphoblastic leukemia [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 4167.
Abstract 2593: Caspase-1 dependent pyroptosis converts αSMA+ CAFs into collagen-III high iCAFs to fuel chemoresistant cancer stem cells
Authors: Hongbo (Beth) Gao, Stephen Q.R. Wong, Ethan Subel, Mustafa Karabicici, Winston Huang, Mark Ellie Alonzo, Keith Syson Chan
Journal: Cancer Research (2025)

Abstract Chemotherapy-induced pyroptotic tumor cells potentially impact on cancer-associated fibroblasts (CAFs), which serve as key cellular components in stroma to construct a favorable tumor microenvironment (TME). Our study identifies three CAFs subtypes: αSMA+IL-6- myofibroblastic CAFs (myCAFs), αSMA-IL-6+ inflammatory CAFs (iCAFs), and hybrid i/myCAFs. Caspase-1 activation in tumor cells release inflammatory chemokines/cytokines, promoting iCAFs formation in a CCR6-dependent manner. Interestingly, the reactive iCAFs, instead of myCAFs, contribute to collagen III expression upon chemotherapy-induced cancer cell pyroptosis. Collagen III-enriched microenvironment preferentially harbors CD44high cancer stem cells (CSCs). Consistently, chemoresistant bladder cancers enhance iCAFs markers and collagen III after neoadjuvant chemotherapy. Thus, chemotherapy-caused pyroptotic cancer cells initiates an iCAFs-CSCs feedforward loop to drive the formation of chemoresistant TME. Citation Format: Hongbo (Beth) Gao, Stephen Q.R. Wong, Ethan Subel, Mustafa Karabicici, Winston Huang, Mark Ellie Alonzo, Keith Syson Chan. Caspase-1 dependent pyroptosis converts αSMA+ CAFs into collagen-III high iCAFs to fuel chemoresistant cancer stem cells [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 2593.
Abstract 7115: PredicineDIRECT: a one-stop “from sample to result” workflow for improved sample management in oncology clinical trials
Authors: Yong Huang, Ao Zhou, Pan Du, Shidong Jia, Qin Luo, Alexander Kuklin, Myles Walsh
Journal: Cancer Research (2025)

Abstract Background: Liquid biopsy is now a standard in clinical trials, improving therapy selection, prognosis, and biomarker discovery. However, reliance on CROs for sample collection, processing, and storage often leads to delays and inefficiencies. PredicineDIRECT, a genomics-based biorepository system, addresses these challenges by centralizing sample management, enabling rapid and accurate support for clinical trials. Methods: Using ISO13485-certified GMP kits, Predicine collects and processes blood, urine, and tissue samples globally and manage samples using BioLIMS. Patient-specific SNP barcodes and bioinformatics analyses detect errors like mislabeling or sample swaps. Tumor Fraction (TF) is measured via low-pass whole-genome sequencing to assess tumor burden efficiently. This workflow enables real-time quality control, longitudinal tumor burden evaluation, and optimized sample selection for downstream analysis. Sponsors access data through a client portal, while securely stored samples remain ready for immediate in-house genomic testing. Results: In a trial cohort, SNP barcoding identified sample mismatches, including one between plasma and buffy coat samples and another at a longitudinal time point. Predicine promptly resolved these discrepancies, communicating actionable solutions to the sponsor before long-term storage. TF analysis of plasma samples revealed molecular progression, guiding selection of key time points for deep sequencing. A case study also demonstrated SNP inconsistencies between plasma and buffy coat samples, highlighting the robustness of PredicineDIRECT’s error-detection system. Conclusion: PredicineDIRECT provides a streamlined, cost-effective solution for clinical trial sample management by centralizing processes in a single laboratory. With integrated SNP barcoding and TF analysis, the system ensures error-free handling, accelerates downstream sequencing, and delivers actionable insights into tumor burden, supporting efficient and informed decisions in oncology trials. Citation Format: Yong Huang, Ao Zhou, Pan Du, Shidong Jia, Qin Luo, Alexander Kuklin, Myles Walsh. PredicineDIRECT: a one-stop “from sample to result” workflow for improved sample management in oncology clinical trials [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 7115.
Abstract 6651: β-catenin-mediated aerobic glycolysis: a marker of poor prognosis in triple-negative breast cancer
Authors: Chandra Prakash Prasad, Sheikh Mohammad Umar, Shruti Kahol, Sandeep R. Mathur
Journal: Cancer Research (2025)

Abstract Aerobic glycolysis has emerged as a crucial regulator of cancer cell migration and metastasis in various cancers including TNBCs. Characterization of molecular pathways associated with increased aerobic glycolysis in TNBCs could provide key mechanistic insights into the regulators of TNBC progression. Here, we demonstrated for the first time the theranostic potential of the β-catenin-PFKP-LDHA-MCT1 axis that drives aerobic glycolysis in TNBCs. β-catenin and related glycolytic proteins (PFKP, LDHA, and MCT1) were analyzed in triple-negative breast cancer (TNBC) patients (n=98) using immunohistochemistry (IHC). Prognostic significance was assessed through Kaplan-Meier survival analysis and Cox regression. Additionally, we compared the efficacy of two β-catenin inhibitors, XAV939 and Axitinib, in suppressing β-catenin-driven aerobic glycolysis in both in vitro and in vivo TNBC models. We showed that β-catenin and its associated glycolytic proteins (PFKP, LDHA, and MCT1) are overexpressed in more than 50% of TNBC cases. Kaplan-Meier survival analysis and Cox regression revealed that elevated β-catenin expression, combined with high levels of other glycolytic proteins (β-catenin+MCT1high; β-catenin+PFKP+MCT1high; β-catenin+LDHA+MCT1high; and β-catenin+PFKP+LDHA+MCT1high), was linked to poor prognosis, highlighting the role of β-catenin-regulated aerobic glycolysis in TNBC aggressiveness. Additionally, we found that Axitinib, compared to XAV939, more effectively reduced β-catenin and glycolytic protein expression, lactate production, cell migration, invasion, and colony formation in TNBC cell lines. In conclusion, this study is the first to identify a novel β-catenin-regulated aerobic glycolysis pathway in triple-negative breast cancer (TNBC). We also demonstrated that Axitinib is a more effective inhibitor of this pathway than XAV939. Citation Format: Chandra Prakash Prasad, Sheikh Mohammad Umar, Shruti Kahol, Sandeep R. Mathur. β-catenin-mediated aerobic glycolysis: a marker of poor prognosis in triple-negative 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 6651.