tbuckley/cabot-search huggingface dataset:
Abstract 5879: An optimized sample-to-result workflow for detection of tumor mutations and immune sequencing in liquid biopsies
Authors: Anagha Kadam, Margaret R. Heider, Chen Song, Jian Sun, Ariel Erijman, Nicholas M. George
Journal: Cancer Research (2025)

Abstract Non-invasive liquid biopsies are helping advance various aspects of disease assessment including early detection, disease monitoring, and therapy selection, while also allowing for improved patient follow-up and economic efficiency over traditional tissue biopsies. Plasma cell-free DNA (cfDNA) applications have recently been adopted in prenatal screening, tumor mutation profiling and post-transplant monitoring. Additionally, combining cfDNA profiling with paired RNA analysis of peripheral blood mononuclear cells (PBMCs) can provide useful insights into biomarkers and immune phenotypes, and present a comprehensive multiomic profile from a single blood draw. Several technical and analytical challenges persist in the liquid biopsy field including immediate preservation of draw time levels of cfDNA, minimizing PBMC lysis during storage, low concentrations of cfDNA with even lower tumor fraction, as well as the need for a higher sensitivity in downstream applications to accurately interpret clinical signals. Here, we present an efficient blood-to-result workflow for tumor-specific mutation detection and immune profiling using contrived samples spiked with known mutation controls. Whole blood was collected in Streck Nucleic Acid BCT enabling preservation of draw time concentration of cell-free nucleic acids and prevention of immune cell lysis. Nucleic acid extraction was performed on the isolated PBMCs and plasma fraction using an optimized protocol for the Monarch Mag Viral DNA/RNA Extraction Kit which features a simplified, magnetic bead-based workflow. Isolated cfDNA was used to prepare sequencing libraries using an optimized library prep workflow to maximize conversion efficiency from cfDNA. Isolated PBMC RNA was utilized to prepare RNA-seq libraries and Immune-seq libraries using the NEBNext UltraExpress RNA Library Prep Kit and NEBNext Immune Sequencing Kit, respectively. Combining these sample storage, extraction, and library prep methods resulted in a high yield of cfDNA libraries with minimal contaminating genomic DNA, enabling improved sequencing data quality, high conversion efficiency, and high sensitivity for clinical research, including detecting spike-in mutations. Transcriptome and immune repertoire profiling from the preserved PBMC in the same blood sample provided complementary biomarker information to enable a comprehensive evaluation of the disease status of these samples. Citation Format: Anagha Kadam, Margaret R. Heider, Chen Song, Jian Sun, Ariel Erijman, Nicholas M. George. An optimized sample-to-result workflow for detection of tumor mutations and immune sequencing in liquid biopsies [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 5879.
Abstract 4438: Role of USP1 in overcoming chemoresistance Independent of BRCA mutation status
Authors: Uday Kumar Surampudi, Prashant Kashinath Bhavar, Partha Pratim Sarma, Anuj Ramesh Kshrisagar, Rishi Rahangdale, Appaji Baburao Mandhare
Journal: Cancer Research (2025)

Abstract The efficacy of chemotherapeutic agents like Cisplatin is often limited by DNA repair mechanisms, including the PARP and USP1, that regulates DNA damage response proteins. In this study, we explore the effects of USP1 inhibition, both alone and in combination with a PARP inhibitor, on DNA repair and cell survival following Cisplatin treatment. Our experiments were conducted in a variety of cell lines, irrespective of their BRCA mutation status, to understand the broad applicability of this therapeutic strategy. Cells were treated with Cisplatin to induce DNA damage, followed by treatment with VRTX531 a USP1 inhibitor and/or a PARP inhibitor assessed by in vitro cell based assays such as cell viability, γH2AX foci formation, and comet assay. Inhibition of USP1 resulted in impaired repair of Cisplatin-induced DNA damage, leading to increased sensitivity to subsequent PARP inhibition, regardless of BRCA mutation status. The combination treatment synergistically enhanced cell death, as evidenced by a significant reduction in cell proliferation and an increase in DNA damage markers. These findings suggest that targeting USP1 in combination with PARP inhibition may be a promising therapeutic strategy to overcome chemoresistance, providing a potential treatment approach for tumors with or without BRCA mutations. Further investigation into the mechanistic underpinnings of this combination therapy is warranted to optimize its clinical application. Citation Format: Uday Kumar Surampudi, Prashant Kashinath Bhavar, Partha Pratim Sarma, Anuj Ramesh Kshrisagar, Rishi Rahangdale, Appaji Baburao Mandhare. Role of USP1 in overcoming chemoresistance Independent of BRCA mutation status [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 4438.
Abstract 1383: A gated hydrophobic funnel within BAX binds long-chain alkenals to potentiate pro-apoptotic function
Authors: Jerry Edward Chipuk
Journal: Cancer Research (2025)

Abstract Mitochondria maintain a biochemical environment that cooperates with BH3-only proteins (e.g., BIM) to potentiate BAX activation, the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-trans-hexadecenal (2t-hexadecenal) is one such component described to support BAX activation, but molecular mechanisms remain largely unknown. Here, we utilize complementary biochemical and biophysical techniques to reveal that 2t-hexadecenal non-covalently interacts with BAX, and cooperates with BIM, to stimulate early activation-associated intramolecular rearrangements prior to membrane permeabilization. Integrated structural and computational approaches suggest 2t-hexadecenal binds an undefined region - a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8 - we term the "BAX actuating funnel (BAF).” Alkenal length and α8 mobility are critical determinants for the interaction, intramolecular rearrangements, and functional outcome of 2t-hexadecenal binding to the BAF; we also present a first-in-class small molecule that functionally mimics 2t-hexadecenal contributions to apoptosis. Collectively, this work imparts detailed molecular insights into how pro-apoptotic BCL-2 proteins and lipids assemble to initiate the mitochondrial pathway of apoptosis, and reveals the therapeutic potential of targeting the BAF. Citation Format: Jerry Edward Chipuk. A gated hydrophobic funnel within BAX binds long-chain alkenals to potentiate pro-apoptotic function [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 1383.
Abstract 1923: A tract of homozygosity analysis reveals methylation-driven <i>CSMD1</i> expression in non-small cell lung cancers
Authors: Jing Jin, Yasir Rahmatallah, Horacio Gomez-Acevedo, Yong-Moon Mark Park, David W. Ussery, Mohammed S. Orloff
Journal: Cancer Research (2025)

Abstract INTRODUCTION: The genetic and epigenetic alterations associated with smoking remain incompletely defined in Non-Small Cell Lung Cancer (NSCLC) carcinogenesis. This study investigates methylation-driven gene expression differences by smoking behaviors in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) using the Tracts of Homozygosity (TOH) approach. METHODS: Genetic, epigenetic, and environmental factors were examined to identify potential methylation-driven genes in NSCLC by subtype and smoking status. The analysis incorporated data from a genome-wide association study (GWAS), the Cancer Genome Atlas Program (TCGA), including methylation arrays/RNA-Seq, and clinical information among European Americans. A TOH block is defined as a string of SNP genotypes that harbor both common and rare variants. Multivariable logistic regression models were used to identify significant genes that also overlapped significant TOH clusters and contained differentially methylated regions (DMRs). A refined analysis was performed to assess methylation status at the probe level for all differentially expressed genes in the overlapping TOH regions and DMRs. Further, the multivariable Cox proportional hazards regression model was used to evaluate the association between gene expression levels and mortality risk. RESULTS: Analysis of differentially expressed genes in TOH regions and DMRs showed hypermethylation at a CpG promoter site (cg08383399) upstream of CSMD1 in smokers with LUAD and negatively correlated with CSMD1 expression (r=-0.18; p=0.004). LUAD smokers with high CSMD1 expression showed better survival probability than those with low CSMD1 expression, especially among those with &amp;gt; 30 pack-years of smoking history (Hazard Ratio: 0.57; 95% Confidence Interval: 0.32, 0.99). In addition, we identified several genes related to smoking-induced inflammation from the list of differentially expressed genes overlapping DMRs and differentially methylated probes in TOH regions. CONCLUSION: The TOH approach identified smoking-associated methylation patterns linked to differentially expressed genes in NSCLC by subtypes. These findings contribute to the identification of smoking-induced biomarkers for NSCLC facilitating personalized screening and suggesting intervention strategies to reduce smoking-related risks. Citation Format: Jing Jin, Yasir Rahmatallah, Horacio Gomez-Acevedo, Yong-Moon Mark Park, David W. Ussery, Mohammed S. Orloff. A tract of homozygosity analysis reveals methylation-driven CSMD1 expression in non-small cell lung 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 1923.
Abstract 5550: Understanding therapy resistance in T-cell acute lymphoblastic leukemia
Authors: Ahmad Nasimian, Kinjal Shah, Julhash U. Kazi
Journal: Cancer Research (2025)

Abstract The deregulation of BCL2 family proteins is a key contributor to the development of T-cell acute lymphoblastic leukemia (T-ALL). Pharmacological inhibition of these proteins, particularly through the BCL2-specific inhibitor venetoclax, has emerged as a promising therapeutic approach. However, the clinical efficacy of venetoclax is often compromised due to primary and acquired resistance mechanisms that remain incompletely understood. We employed a deep tabular learning algorithm to develop a drug sensitivity prediction model using T-ALL patient samples. Our findings revealed distinct expression profiles between drug-sensitive and drug-resistant samples. Specifically, in the context of venetoclax sensitivity and resistance phenotypes, we observed associations with several key proteins regulating the cell cycle, cytokine signaling, and mitochondrial apoptosis. Our data suggest a key link between lipid metabolism and beta-catenin signaling, which may cooperate with transcription factors regulating the transcriptional activation of key apoptosis regulatory genes. Together, our results underscore the complexity of therapy resistance and highlight the therapeutic potential of targeting multiple pathways for growth inhibition. Future research should focus on clinical trials exploring this combinatorial approach to overcome resistance and improve patient outcomes in T-ALL. Citation Format: hmad Nasimian, Kinjal Shah, Julhash U. Kazi. Understanding therapy resistance in T-cell 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 5550.
Abstract 5532: Combinational targeted therapy effects on EphA2 and KRAS G12C inhibitor against KRAS G12C mutated non-small cell lung cancer cells
Authors: Hayato Kawachi, Tadaaki Yamada, Yuki Katayama, Takayama Koichi
Journal: Cancer Research (2025)

Abstract Background: KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), and some KRAS G12C inhibitors have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, these KRAS G12C inhibitors have shown limited efficacy, and developing novel treatment strategy is warranted to improve clinical prognosis in this clinical population. EphA2, a receptor tyrosine kinase overexpressed in various cancers including NSCLC, plays a critical role in tumorigenesis and cancer progression, with high expression levels associated with poor prognosis. Recent studies indicate that targeting EphA2 can effectively inhibit tumor growth and induce apoptosis in KRAS-mutated NSCLC, underscoring its potential as a promising therapeutic target. Methods: In this preclinical study, we investigated the combined effect and underlying mechanisms of KRAS G12C inhibitors and EphA2 inhibition using multiple human KRAS G12C-mutated lung cancer cell lines. Results: The combined inhibition of KRAS G12C and EphA2 resulted in enhanced suppression of cell proliferation via increasing cell apoptosis in a subset of these KRAS G12C-mutant lung cancer cells. The KRAS G12C and EphA2 inhibitor combination also suppressed cell migration, compared with the effects in each monotherapy. Cell line-derived xenograft model indicated that the combination of KRAS G12C inhibitor plus EphA2 inhibitor enhanced anti-tumor effects compared with KRAS G12C inhibitor monotherapy. Further examination of apoptosis-related proteins revealed that the combination treatment reduced Mcl-1 expression. Additionally, combining KRAS G12C with an Mcl-1 inhibition led to further increases in cell death and enhanced suppression of cell proliferation. Conclusions: The combination of KRAS G12C inhibitors and EPhA2 inhibition is expected as the promising strategy for those tumors. Citation Format: Hayato Kawachi, Tadaaki Yamada, Yuki Katayama, Takayama Koichi. Combinational targeted therapy effects on EphA2 and KRAS G12C inhibitor against KRAS G12C mutated non-small cell lung cancer 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 5532.
Abstract 3426: Preclinical development of CD-001, a novel fusion protein combining PD-1 blockade with IL-21 for solid tumors
Authors: Ying Li, Xiao Luan, Shaonan Zhou, Xiangrui Cheng, Jitao Zhao, Guoju Sang, Hao Shen, Naibo Yang, Junjie Yang, Jian Xu, Shengdian Wang
Journal: Cancer Research (2025)

Background: Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy, offering significant clinical benefits. However, these successes are unfortunately limited to a minority of patients. Meanwhile, cytokine-based therapies have shown promise in cancer treatment, but are accompanied by potential severe systemic toxicity. CD-001 is a novel fusion protein integrating anti-PD-1 antibody with mutated IL-21. This dual-targeting approach enables simultaneous blockade of the PD-1/PD-L1 axis and targeted delivery of IL-21 to PD-1+ T cells, aiming to enhance tumor-specific immune responses while minimizing systemic adverse effects. Methods: Comprehensive nonclinical studies, including pharmacology, pharmacokinetics (PK), and toxicology assessments, were conducted to evaluate the safety and efficacy of CD-001. Pharmacology studies were performed to assess CD-001’s binding affinity to PD-1 and IL-21R as well as its functional targeting of PD-1+ T cells. In vivo efficacy was explored in various mouse tumor models including melanoma, lung cancer, and lymphoma. Toxicology and PK were also evaluated in cynomolgus monkeys. Results: CD-001 exhibited high affinity to both PD-1 and IL-21R, and effectively targeted PD-1+ T cells to exert its biological function. In vivo, CD-001 demonstrated superior antitumor activity compared to anti-PD-1 monotherapy or its combination with IL-21. Enhanced tumor-reactive CD8+ T cell responses were observed. PK studies showed dose-proportional systemic exposure of CD-001 with no significant accumulation after repeated dosing in cynomolgus monkeys, and receptor occupancy results illustrated more than 30% of target engagement within 7 days. GLP toxicity studies in cynomolgus monkeys demonstrated a favorable toxicity profile, with no significant cardiovascular or neurological dysfunctions observed. Immunotoxicity observed in the GLP study tended to resolve or was fully resolved by the end of the recovery period. Conclusion: CD-001 exhibits a well-characterized safety profile and potent antitumor activity in preclinical models, supporting its future development as a therapeutic candidate for advanced solid tumors. The dual mechanism of CD-001, combining PD-1 inhibition with targeted IL-21 delivery, represents a novel therapeutic strategy to enhance T cell-mediated immunity in cancer patients. Citation Format: Ying Li, Xiao Luan, Shaonan Zhou, Xiangrui Cheng, Jitao Zhao, Guoju Sang, Hao Shen, Naibo Yang, Junjie Yang, Jian Xu, Shengdian Wang. Preclinical development of CD-001, a novel fusion protein combining PD-1 blockade with IL-21 for 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 3426.
Abstract 3871: Methyl jasmonate reduces proliferation and migration of head and neck cancer cell lines
Authors: Jorge Viera-Vera, María M. Sánchez-Vázquez, Nicole J. Sariego-Hassan, Adianez Rosario-Vázquez, Magaly Martínez-Ferrer
Journal: Cancer Research (2025)

Abstract Head and neck squamous cell carcinomas (HNSCC) arise from the mucosal lining of the oral and nasal cavities, pharynx, and larynx. The 2022 Global Cancer Statistics identify HNSCC as the sixth most common and seventh most lethal cancer globally, with 891, 453 new cases and 458, 107 fatalities. Over half of patients with HNSCC are diagnosed at an advanced stage, this has been associated with difficulties in early diagnosis, tumors with significant local invasion, and metastases in regional nodes. The Surveillance, Epidemiology, and End Results Program (SEER) estimates about 54, 000 new HNSCC cases and 11, 230 deaths in the United States during 2022, contributing to approximately 2% of all cancer deaths. The 5-year survival varies by stage at diagnosis, fluctuating from 86.3% for localized disease to 40.4% for metastatic disease. Current treatments for HNSCC include surgery, radiation, and chemotherapy, which can lead to serious side effects and may offer limited efficacy. Researchers have recently focused on exploring new complementary therapies. This study aims to analyze how methyl jasmonate (MeJa) affects HNSCC cell lines A-253 and SCC9 with special emphasis on cell migration. Methyl jasmonate is a plant-derived hormone that has been proven to exhibit highly selective cytotoxicity toward cancer cells that may prove to be a potentially less toxic therapeutic agent. The half maximal effective concentration (EC50) for MeJa was determined employing the MTS Assay Colometric Kit (Abcam, USA) and following the manufacturer instructions. Wound healing assays using the scratch method were performed and image data was collected with an Olympus LC35 camera attached to an CKX53 microscope. All experiments were performed in triplicates and data was analyzed using GraphPad Prism. MeJa inhibited the proliferation of A-253 and SCC9 HNSCC cell lines in a dose-dependent manner with estimated IC50 values of 2.23µM and 2.05µM respectively. Furthermore, the wound healing assay showed that MeJa significantly decreased cell migration in the A-253 cell lines at 12 and 24 hours after treatment. Our findings support the potential effects of methyl jasmonate on cellular events such as cell proliferation and migration during tumor progression of head and neck squamous cell carcinomas. Citation Format: Jorge Viera-Vera, María M. Sánchez-Vázquez, Nicole J. Sariego-Hassan, Adianez Rosario-Vázquez, Magaly Martínez-Ferrer. Methyl jasmonate reduces proliferation and migration of head and neck cancer cell lines [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 3871.
Abstract 5179: Investigating the tumor suppressive role of RanBP9 in mice deficient in p53
Authors: Brianna Gonga-Cave, Gabriel Onea, Xu Wang, Sean Cregan, Patti Kaiser, Caroline Schild-Poulter
Journal: Cancer Research (2025)

Abstract RAN binding protein 9 (RanBP9) is a scaffolding protein that is essential for the formation a multi-subunit E3 ubiquitin ligase termed the C-terminal to Lis-1 homology (CTLH) complex. Multiple groups have identified the CTLH complex in regulating a broad range of biological processes including cell cycle, cell proliferation, and metabolism. Various studies have demonstrated that RanBP9 functions as a tumor suppressor, but none have shown whether the loss of RanBP9 can initiate spontaneous tumor formation. Here, we investigated the tumor suppressive role of RanBP9 in C57BL/6 mice. Bulk RNA sequencing (RNA-seq) analysis of 1-month-old RanBP9-/- mice liver identified an upregulation of several oncogenic signaling genes. Although RanBP9-/- mice displayed a shortened lifespan, these mice did not develop spontaneous tumors suggesting that additional genetic perturbations are required for tumor development. Next, we conducted an observational study in mice with RanBP9+/-: Trp53+/- (R9; p53+/-) and RanBP9-/-: Trp53-/- (R9; p53-/-) genotypes. These mice were monitored over 17 months for the development of spontaneous tumors. The primary endpoint was defined as the development of a visible mass (&amp;gt;1.5 cm) or symptoms of cancer. R9; p53+/- mice (n=23) developed sarcomas at an earlier time compared to control p53+/- mice (n=18; p&amp;lt;0.05). R9; p53+/- mice displayed altered tumor spectrum with increased frequency in soft tissue sarcoma (STS) development. H&amp;E analysis of tumor biopsies revealed increased mitotic activity of sarcomas derived from R9; p53+/- mice compared to control p53+/- mice. We observed no significant difference in tumor incidence and altered tumor spectrum in R9; p53-/- mice compared to control p53-/- mice. Analysis of TCGA sarcoma database revealed a correlation between low gene expression of CTLH complex genes and reduced survival in sarcoma patients. Our data indicates that loss of RanBP9 alone is insufficient to initiate tumor development. However, the heterozygous loss of RanBP9 and p53 promotes increased STS development. Ongoing efforts are to further characterize R9; p53+/- tumors and identify the mechanism to understand how the loss of CTLH activity contributes to sarcoma development in the absence of p53. Our findings may support the development of anti-cancer therapeutics that activates RanBP9-CTLH complex activity. Citation Format: Brianna Gonga-Cave, Gabriel Onea, Xu Wang, Sean Cregan, Patti Kaiser, Caroline Schild-Poulter. Investigating the tumor suppressive role of RanBP9 in mice deficient in p53 [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 5179.