tbuckley/cabot-search huggingface dataset:
Abstract 6201: The factors influencing quality of life among patients with hepatobiliary and pancreatic cancers
Authors: Sieun Lee, Sunhee Hwang, Junglyun Kim
Journal: Cancer Research (2025)

Abstract Background: Hepatobiliary and pancreatic cancers are aggressive malignancies with poor survival rates, largely due to challenges in early diagnosis and limited curative treatment options. These cancers significantly impact patients' quality of life (QOL), which is strongly associated with treatment outcomes and overall survival. Despite its importance, comprehensive research on QOL in these patients remains limited, highlighting the need to identify factors influencing QOL to improve care and outcomes. The purpose of this study is to identify the factors influencing the QOL among patients with hepatobiliary and pancreatic cancers. To describe comprehensive factors associated with QOL, we applied the biopsychosocial model (Engel, 1977) in the study. The study examined comprehensive clinical data, which included individuals’ characteristics, symptom assessment, and medical information. Methods: The patients with hepatobiliary or pancreatic cancers were recruited from a university hospital between September 2022 and November 2023. Along with collecting medical and treatment information, pain, depression, anxiety, and QOL were assessed using the Numeric Rating Scale, Hospital Anxiety and Depression Scale, and Functional Assessment Cancer Therapy-General, respectively. Multiple regression analysis was performed to identify factors influencing the QOL using SPSS 26.0. Results: Among the 204 participants, the mean age was 66.7 (±8.52) years old;141(69.1%) were males; 107(52.5%) were diagnosed with liver cancer. Depression, anxiety, pain, and serum albumin significantly influenced the QOL, explaining 68.1% of the variance. Patients who were employed or had no metastasis reported significantly higher QOL. Patients who had higher albumin, lower pain, depression, and anxiety reported higher QOL. These findings emphasize the need for psychosocial support, pain management, and nutritional care to improve the QOL in patients with hepatobiliary and pancreatic cancers. Conclusions: To improve the QOL of patients with hepatobiliary and pancreatic cancers, we suggest providing appropriate psychosocial support, pain control, and nutritional management during the cancer treatment. Citation Format: Sieun Lee, Sunhee Hwang, Junglyun Kim. The factors influencing quality of life among patients with hepatobiliary and pancreatic 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 6201.
Abstract 5578: Role of differentiation driver gene HOXD4 in anaplastic thyroid cancer
Authors: Kaci Kopec, Nicole R. DeSouza, David Garber, Steven A. Hemmerdinger, Augustine Moscatello, Humayun K. Islam, Jan Geliebter, Raj K. Tiwari
Journal: Cancer Research (2025)

Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive subset of thyroid cancer, noted for its refractory nature and poor prognosis. Conventional cancer treatments are ineffective in treating ATC while targeted therapies are of limited use due to a lack of targetable genetic lesions in this cancer type thus rendering a five-year survival rate of 4%. The low mutational burden of ATC prompted analysis of differential gene expression patterns using NCBI Gene Expression Omnibus publicly available transcriptomic datasets (GSE33630, GSE85457). Bioinformatic analysis of ATC compared to normal thyroid cancer tissue was carried out using GEO2R software. Strikingly, differentiation driver gene Homeobox D4 (HOXD4) was significantly upregulated in ATC patient tissue samples by 3-fold and 12-fold respectively. Kaplan-Meier analysis indicates a significant decrease in survival in patients with high HOXD4 levels (HR: 3.08, logrank: 0.019). Unlike most cancers, ATC lacks differentiation therefore losing its thyroid-like morphology and function. Thus, the marked upregulation of differentiation gene HOXD4 warranted further exploration in vitro. HOXD4 expression was upregulated in ATC cell line T238 by 23-fold compared to immortalized “normal” thyroid epithelial cell line Nthy-ori-3-1. CRISPRi knockdown of HOXD4 in T238 and SW1736, another ATC cell line, was needed for functional analysis rendering HOXD4 knockdown cell lines T238-HOX and SW1736-HOX as well as non-specific oligonucleotides control cell line. Cell proliferation was reduced in T238-HOX by 36%, 29%, 28%, and 38% and SW1736-HOX by 51%, 56%, 59%, and 52% at 24, 48, 72, and 96 hours respectively. Migratory capacity measured via scratch wound assay was significantly reduced in T238-HOX by 31% and 13% and SW1736-HOX at 45% and 22% at 16 and 22 hours respectively. Migration through Boyden chambers decreased by 72% in T238-HOX and 62% in SW1736-HOX and invasion was reduced by 40% and 51% respectively. We are currently evaluating the impact of HOXD4 knockdown on viability, clonogenicity, and senescence. The data reveal the novelty of HOXD4 as a putative carcinogenic driver of ATC and its function as both a diagnostic and prognostic biomarker, with the potential to be used as a therapeutic target. We are currently investigating various differentiating agents and their efficacy in a possible clinical application with or without other therapeutic agents. Citation Format: Kaci Kopec, Nicole R. DeSouza, David Garber, Steven A. Hemmerdinger, Augustine Moscatello, Humayun K. Islam, Jan Geliebter, Raj K. Tiwari. Role of differentiation driver gene HOXD4 in anaplastic thyroid 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 5578.
Abstract 7066: RING1 inhibits smoking-induced lung cancer tumorigenesis by ubiquitination and degradation of CIP2A
Authors: In-ho Jeong, Peter Chang Whan Lee
Journal: Cancer Research (2025)

Abstract Lung cancer is the second incidence rate of all new cancer diagnoses and the leading cause of cancer-related deaths globally. To develop novel diagnostic and therapeutic targets for lung cancer, there are emerging needs for molecular biological research on the occurrence and progression. Among the targets, CIP2A has been studied for promoting various cancer types, but detailed underlying mechanisms are needed to be further investigated. In this study, it was verified that CIP2A is overexpressed in lung cancer tissues, particularly amongst those with a smoking history, compared to adjacent normal tissues. CIP2A knockdown in lung cancer cells efficiently reduced cell proliferation and migration capacity. Through the mass spectrometry analysis on A549 cells overexpressing CIP2A, RING1 was identified as a candidate for E3 ligase of CIP2A. The interaction of the two proteins and ubiquitin chain regulation by RING1 was verified by immunoprecipitation. RING1 knockdown enhanced proliferation and migration of lung cancer cells, and these effects result from the upregulation of CIP2A and its downstream molecules, c-Myc and cyclin B1. To further study a trigger for RING1 expression changes in lung tumorigenesis, cigarette smoke extract (CSE) was applied for the following experiments. CSE treatment depleted RING1 mRNA, including protein expression. Decreased RING1 level led to upregulation of CIP2A and c-MYC. Collectively, these results reveal novel roles of the RING1 and CIP2A in lung cancer progression caused by smoking and propose a potential biomarker candidate for the therapeutic and diagnostic targets. Citation Format: In-ho Jeong, Peter Chang Whan Lee. RING1 inhibits smoking-induced lung cancer tumorigenesis by ubiquitination and degradation of CIP2A [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 7066.
Abstract 5118: Ectopic expression of cathepsin G in mammary tumor cells and its role in tumor growth and osteolytic bone metastasis
Authors: Ridhi Bhola, Reegan Sturgeon, Rakesh K. Singh
Journal: Cancer Research (2025)

Breast cancer has a high propensity to metastasize to the bone microenvironment. The resulting lesions are predominantly osteolytic and are associated with patient morbidity and mortality. We have demonstrated that tumor-bone interaction plays an important role in osteolytic bone metastasis mediated by the dysregulation of a unique set of genes. Among these genes, several proteases are up-regulated at the tumor-bone interface, including Cathepsin G, a serine protease. These proteases act as mediators between the tumor and stroma. Previously, we have shown that both malignant cells and osteoclasts at the TB interface express higher levels of Cathepsin G, which is critical for osteolytic bone metastasis. The precise role of tumor and/or host-derived Cathepsin G in osteolytic bone metastasis is unknown. In this report, we examined the contribution of tumor-derived Cathepsin G by testing the hypothesis that ectopic expression of Cathepsin G modulates malignant cell phenotype, osteoclast recruitment and activation, and osteolytic metastasis. We generated stable mammary tumor cell lines constitutively expressing Cathepsin G (Cl66-CTSG). Cathepsin G-expressing tumor cells showed diminished in vitro cell proliferative potential and in vivo mammary fat pad tumor growth as compared to vector control transfected Cl66-CMV cells. We demonstrated that Cathepsin G-overexpressing tumor cells induced osteoclast activation and differentiation in vitro and tumor-induced osteolysis in vivo. To observe the morphological changes in tumor cells by CTSG, we performed phalloidin staining and live cell imaging using CTSG-treated tumor cells. We observed that CTSG induced the formation of homotypic aggregations of tumor cells. We found that increasing the concentration of CTSG decreases tumor cell proliferation and increases cell cycle arrest. Our data suggest that tumor-derived Cathepsin G might have distinct tumor-modulating activities in the bone microenvironment by regulating cell proliferation and osteoclast recruitment and activation. Citation Format: Ridhi Bhola, Reegan Sturgeon, Rakesh K. Singh. Ectopic expression of cathepsin G in mammary tumor cells and its role in tumor growth and osteolytic bone metastasis [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 5118.
Abstract 5106: Cell crowding-induced TRPV4 inhibition and relocation to plasma membranes: Implications for a pro-invasive mechanotransduction pathway in DCIS progression
Authors: Xiangning Bu, Nathanael Ashby, Teresa Vitali, Sulgi Lee, Ananya Gottumukkala, Kangsun Yun, Sana Tabbara, Patricia Latham, Christine Teal, Inhee Chung
Journal: Cancer Research (2025)

Cell crowding is a common microenvironmental factor influencing disease progression, yet its role in promoting cell invasiveness remains poorly understood. Here, we demonstrate that cell crowding enhances the invasiveness of high-grade ductal carcinoma in situ (DCIS) cells through pro-invasive cell volume reduction. High-grade DCIS cells showed significant volume reduction compared to hyperplasia-mimicking or normal cells under crowded conditions. Mass spectrometry revealed selective relocation of TRPV4, a calcium-permeant ion channel, to the plasma membrane in high-grade DCIS cells, a response absent in less aggressive or normal cells. We found that cell crowding inhibits TRPV4 activity in high-grade DCIS cells, reducing intracellular calcium levels and inducing volume reduction. This inhibition triggers TRPV4 relocation to the plasma membrane, priming it for subsequent activation to counterbalance calcium loss. Analyses of patient-derived breast cancer tissues confirmed TRPV4 association with the plasma membrane specifically in high-grade DCIS, correlating with increased cell invasiveness and motility. Moreover, hyperosmotic stress and pharmacologic TRPV4 inhibition replicated crowding-induced pro-invasive volume reduction, while TRPV4 activation reversed these effects. These findings uncover a novel, selective mechanotransduction pathway in high-grade DCIS that links cell crowding to enhanced invasiveness, shedding light on the biophysical mechanisms driving breast cancer progression. Our results highlight TRPV4 as a potential diagnostic and prognostic biomarker for high-risk DCIS and provide insights into therapeutic interventions targeting cell volume regulation. Citation Format: Xiangning Bu, Nathanael Ashby, Teresa Vitali, Sulgi Lee, Ananya Gottumukkala, Kangsun Yun, Sana Tabbara, Patricia Latham, Christine Teal, Inhee Chung. Cell crowding-induced TRPV4 inhibition and relocation to plasma membranes: Implications for a pro-invasive mechanotransduction pathway in DCIS progression [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 5106.
Abstract 2499: Precision oncology empowered: A web platform for population pharmacokinetic modeling
Authors: Ahmed Fadiel
Journal: Cancer Research (2025)

Abstract Background: More than 85% of oncology clinical trial failures are due to problems in pharmacokinetics, pharmacodynamics, and inter-patient variability. In cancer research, therapeutic windows are narrow, and inability to predict drug responses across genetically and clinically diverse populations further complicates the problem. Population pharmacokinetics thus provides a solution by characterizing variability and optimizing dosing; however, it is not yet widely adopted in translational oncology because of technical complexity. Herein, we describe an advanced web-based platform that streamlines PPK model creation, validation, and simulation to optimize trial design and therapy selection in oncology. Methods: Advanced computational approaches tailored for cancer drug development are integrated into the platform. Hierarchical parameterizations for fixed effects, random effects, and residual error structures enable precise modeling of drug behavior in oncology settings. Hybrid estimation techniques combine stochastic approximation and nonlinear mixed-effects optimization for robust parameter convergence in high-dimensional cancer datasets. Real-time diagnostic plots and multi-dimensional parameter exploration refine models iteratively. Virtual trial simulations incorporate demographic and genetic heterogeneity to predict drug responses and optimize dosing strategies. Results: The platform validated, with high accuracy, a one-compartment PK model for an anti-cancer agent. Virtual trial simulations demonstrated variability in dose-response across subgroups of cancer patients and identified strategies to optimize therapeutic windows. The platform reduced computational complexity, improved precision, and enabled rapid iteration of complex models. Simulations of alternative trial scenarios identified opportunities to refine inclusion criteria and dosing strategies, offering potential to reduce oncology trial failure rates. Conclusion: This platform now offers sophisticated tools to tackle the most relevant challenges in drug development against cancer, thus allowing more successful clinical trials and personalized treatments. It is a quantum leap in precision oncology through the in-silico simulation of drug responses and optimization of trial parameters. Currently available internally, the tool will be broadly distributed following further validation. Citation Format: Ahmed Fadiel. Precision oncology empowered: A web platform for population pharmacokinetic modeling [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 2499.
Abstract 5645: Targeting transcription-replication conflict for selective chemotherapy in glioblastoma
Authors: Long Gu, Robert J. Hickey, Linda H. Malkas
Journal: Cancer Research (2025)

Abstract The current standard of care for glioblastoma (GBM) is surgical intervention followed by a combination of temozolomide (TMZ) and radiation therapy. Only 5% GBM patients survive more than five years despite aggressive therapeutic treatment. A significant hurdle to develop target-based therapies for GBM is the complexity and diversity of the disease. Genomic and epigenetic profiling has found a broad range mutational and transcriptional events across this histologically diverse disease. A hallmark of GBM is genomic instability, which is a key factor in its progression and complexity. The fast growing and aggressive GBM cells demand rapid DNA replication and hypertranscription, leading to enhanced transcription-replication conflicts (TRCs). A major source of genomic instability, TCR causes lethal double stranded DNA breaks (DSBs) if not resolved properly. We hypothesize that enhanced TRC is a weak link and a promising target for treating GBM. Proliferating cell nuclear antigen (PCNA) is a key component of DNA replication machinery and plays an essential role in the DNA replication and repair. Through a rational drug design, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. Mechanistically, AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions. By interfering with TRC resolution as evidenced by induction of R-loop levels in cancer cells, AOH1996 induces DSBs in a transcription-dependent manner. Orally administrable and metabolically stable, AOH1996 can freely pass the blood brain barrier and enter brain tumors. Here, we report that it selectively kills GBM cells as a monotherapy or in combination with TMZ but causes no discernable side effects. Importantly, AOH1996 targets a cancer specific region of PCNA that is a highly conserved through evolution and influences the activity of broad cellular processes that are essential to the growth and survival of cancer cells. GBM cancer cells are, therefore, less likely to develop resistance to AOH1996 through mutagenesis in PCNA. If combined with the existing chemotherapeutic regime and inhibitors of DNA repair pathways, AOH1996 may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability to deliver a durable response in GBM. Citation Format: Long Gu, Robert J. Hickey, Linda H. Malkas. Targeting transcription-replication conflict for selective chemotherapy in glioblastoma [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 5645.
Abstract 5576: Identification of inter-organ targets to mitigate cachexia while enhancing tumor suppression by anti-PD-L1
Authors: Se-Young Park, Jiwoo Kim, Kyuwon Son, Haeseung Lee, Na-Young Song
Journal: Cancer Research (2025)

Immune checkpoint inhibitors (ICIs), such as anti-PD-L1, have revolutionized cancer therapy but are frequently associated with immune-related adverse events (irAEs). Here, we show a significant correlation between ICI treatment and weight loss in cancer patients. Similarly, anti-PD-L1 therapy exacerbates muscle wasting in a cancer cachexia (CAC) mouse model, despite its anti-tumor effects, suggesting that muscle atrophy may represent a potential irAE. Single-cell RNA sequencing reveals that cytotoxic T-like cells accumulate in the skeletal muscle of CAC mice, directly contributing to muscle wasting. While their depletion prevents cachexia, it compromises the anti-tumor efficacy of anti-PD-L1. To address this discrepancy, we identify cathepsin L (CTSL) as an inter-organ target capable of inhibiting both cancer and cachexia, particularly muscle wasting driven by cytotoxic T cells, through unbiased integrative transcriptome analysis. Notably, CTSL inhibition not only reduces muscle wasting but also enhances the anti-tumor efficacy of anti-PD-L1. These findings highlight CTSL as a promising therapeutic target for cancer cachexia, offering a novel strategy to prevent muscle-specific irAEs while enhancing the benefits of ICIs. Citation Format: Se-Young Park, Jiwoo Kim, Kyuwon Son, Haeseung Lee, Na-Young Song. Identification of inter-organ targets to mitigate cachexia while enhancing tumor suppression by anti-PD-L1 [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 5576.
Abstract 5592: Modeling response prediction to a novel GCN2 kinase activator (NXP800) in patient-derived xenograft cholangiocarcinoma models using a multi-omics approach
Authors: Danielle Marie Carlson, Hendrien Kuipers, Amro Abdelrahman, Erik Jessen, Joshua Roldan Kalill, Jennifer Tomlinson, Jack Sample, Akhilesh Pandey, Mark Truty, Rory Smoot
Journal: Cancer Research (2025)

Abstract Introduction: Cholangiocarcinoma (CCA) is an aggressive biliary malignancy with poor survival outcomes and multiple mechanisms of resistance to targeted therapies. We previously validated NXP800, a novel GCN2 small-molecule activator, as an effective anti-cancer drug in six CCA cell lines. In vitro testing identified upregulation of phosphorylated eIF2a, as well as upregulation of ATF4, in CCA cells treated with of NXP800 compared to vehicle, suggesting that treated cells led to stimulation of stress-induced genes and subsequently, apoptosis. Furthermore, patient derived xenografts (PDX) models treated with NXP800 were found to have decreased tumor size, particularly in models containing ARID1A, FGFR1, and ATM mutations. Here, we aimed to predict response to NXP800 using sensitivity and resistance signatures from our profiled PDX models. Methods: GCN2 activation in multiple previously profiled PDX models was evaluated. Whole Exome Sequencing (WES) was done on multiple PDX models to characterize the mutational signature and activity in CCA. Two additional CCA xenografts were expanded into the flank of NOD/SCID mice. Tumor bearing mice were treated with NXP800 (35 mg/kg) or vehicle via oral gavage for 28 days once tumors averaged 120 mm3. Tumor volume and animal weight were collected twice weekly. Median Efficacy Index (MEI) scores were generated as drug response rates based on tumor growth. Predicted sensitivity and resistance kinase signatures to predict drug response were produced using multi-omics. Results: Treatment with NXP800 was associated with a statistically significant decrease in tumor size in two additional PDX models, which included ARID1A and BRAF mutants. Preliminary multi-omics on the PDX models revealed that sensitivity mechanisms were upregulated most in EGFR signaling, while resistance signatures were focused around CSNK2A1 signaling. Conclusion: Multi-omics analysis revealed a sensitivity mechanism structured around EGFR signaling, providing insights into which patients should be selected for treatment with NXP800. A Phase 1b clinical trial investigating the effects of NXP800 use in patients with advanced CCA is open and currently accepting patients. Citation Format: Danielle Marie Carlson, Hendrien Kuipers, Amro Abdelrahman, Erik Jessen, Joshua Roldan Kalill, Jennifer Tomlinson, Jack Sample, Akhilesh Pandey, Mark Truty, Rory Smoot. Modeling response prediction to a novel GCN2 kinase activator (NXP800) in patient-derived xenograft cholangiocarcinoma models using a multi-omics approach [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 5592.