tbuckley/cabot-search huggingface dataset:
Abstract A017: Enhanced efficacy of anti-mesothelin CAR T cells in ovarian cancer through drug combinations: Impact of treatment kinetics, co-stimulatory domain, and donor variability
Authors: Lucía Rico Pizarro, Thomas Poiret, Greta Gudoitytė, Olli Kallioniemi, Brinton Seashore-Ludlow, Isabelle Magalhaes, Tom Erkers
Journal: Cancer Research (2025)

Abstract Introduction: Clinical trials of mesothelin (MSLN) chimeric antigen receptor (CAR) T-cell therapy have shown limited efficacy in solid tumors like ovarian cancer (OVCA), emphasizing the need to enhance CAR T cell performance. This study evaluated whether combining MSLN-CAR T cells with drugs, either sequentially or concurrently, could achieve synergistic anti-tumor effects. Methods :MSLN-directed CAR T cells were generated using two constructs with CD28 (M28z) or 4-1BB (MBBz) co-stimulatory domains. A high-throughput drug screen of 528 compounds was conducted on MSLN-expressing OVCA cells in combination with CAR T cells, assessing three conditions: (1) simultaneous drug and CAR T exposure, (2) short drug pre-treatment of OVCA, and (3) extended drug pre-treatment before CAR T cell introduction. Drug-induced modulation of CAR T cell cytotoxicity was assessed by comparing CAR T cell-mediated killing, drug-only effects, and drug-CAR T cell combination effects on OVCA cells. Results: Synergy between drugs and CAR T cells depended on treatment timing and co-stimulatory domains. Chemotherapeutics enhanced CAR T cell cytotoxicity when administered as a pre-treatment, while epigenetic modulators and kinase inhibitors were more effective with concurrent CAR T cell application. Cisplatin and cytarabine significantly boosted MBBz CAR T activity, while idarubicin enhanced M28z CAR T cells. Certain agents, like vinflunine, gemcitabine, and the PARP inhibitor rucaparib, enhanced efficacy across both constructs. Donor-specific responses revealed two distinct donor clusters: one showed synergy with chemotherapeutics, and the other with targeted agents Conclusions: Combining drugs with CAR T cell therapy could improve the treatment efficacy in ovarian cancer. Pre-treatment with specific chemotherapeutics enhanced CAR T cell cytotoxicity, while simultaneous treatment with certain targeted therapies was also effective. The effects of CAR construct type and inter-donor variability highlight the potential for precision medicine approaches. These findings support further exploration of personalized therapeutic combinations to optimize CAR T cell efficacy in ovarian cancer and improve patient outcomes. Citation Format: Lucía Rico Pizarro, Thomas Poiret, Greta Gudoitytė, Olli Kallioniemi, Brinton Seashore-Ludlow, Isabelle Magalhaes, Tom Erkers. Enhanced efficacy of anti-mesothelin CAR T cells in ovarian cancer through drug combinations: Impact of treatment kinetics, co-stimulatory domain, and donor variability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A017.
Abstract A010: Performance of colorectal cancer genetic risk scores and its utility in recall by genotype in East Asians
Authors: Abram Bunya Kamiza, Chih-Ching Yeh
Journal: Cancer Research (2025)

Abstract Background: Polygenic risk scores (PRSs) have potential for clinical utility. However, their performance and predictability have been inconsistent. This study aimed to assess the performance and predictability of PRSs for colorectal cancer (CRC) in East Asians and use PRSs to perform a recall by genotype (RbG) to assess the causality. Methods: Genome-wide association summary statistics for PRSs construction were obtained from Biobank Japan (BBJ), Korean Genomic Epidemiology Study (KoGES), and East Asian Colorectal Cancer Consortium (EACCC). The target cohort for PRSs development were obtained from Taiwan and Taipei Medical University Biobanks. PRSs were constructed using PRIScie. Individuals with high and low PRSs for cigarette smoking and alcohol consumption were classified as “high risk” and “low risk,” respectively and used in RbG. We validated our RbG findings using a Mendelian randomization (MR). Results: The most predictive PRSs were derived from EACCC and individuals in the top 10% of the decile had an increased risk of CRC (odds ratio [OR] = 2.11, 95% confidence interval [CI] = 1.44-3.12, P = 0.000149) compared to those in the bottom decile. Using RbG, we found that cigarette smoking (OR = 1.61, 95% CI = 1.20-2.16, P = 0.00136) and alcohol consumption (OR = 1.85, 95%CI = 1.09-3.04, P = 0.01871) to be causally associated with CRC. Moreover, our RbG findings were replicated MR approaches. Conclusion: PRSs derived from EACCC performed better than PRSs derived from BBJ and a meta-analysis of the KoGES and BBJ. Our RbG and MR analyses found cigarette smoking and alcohol consumption to be causally associated with CRC. Citation Format: Abram Bunya Kamiza, Chih-Ching Yeh. Performance of colorectal cancer genetic risk scores and its utility in recall by genotype in East Asians [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A010.
Abstract B035: Evaluating drug sensitivity heterogeneity in cancer organoids derived from circulating tumor cells
Authors: Yi-chun Han, David Hsieh, Shian-Jiun Shih
Journal: Cancer Research (2025)

Abstract Background: Drug resistance is a major challenge in cancer treatment, often driven by tumor cell heterogeneity. We cultivated circulating tumor cells (CTCs) from the blood of patients with solid tumors, including those preserved as frozen PBMCs, into cancer organoids. Two organoid lines, derived from renal and colon cancers, have been maintained and used extensively to assess drug sensitivity. During these experiments, viability assays revealed that a subset of organoids displayed resistance to certain drugs, resuming growth after initial inhibition. This prompted us to investigate this heterogeneity using specialized assays. Methods: To study variability in drug responses among CTC-derived organoids, we employed three complementary approaches: 1. Microcavity Plates: Corning's Elplasia plates with microcavities were used to segregate organoids, facilitating high-resolution, kinetic imaging for monitoring individual organoid growth and survival during drug treatment. 2. Image Analysis: Morphological changes in organoids during drug exposure were tracked using image analysis, allowing for the quantitation of resistant organoids and providing insights into variations in growth patterns and morphological changes. 3. Transcriptome Profiling: Using individual organoids, each with sufficient RNA for analysis, allowed detailed transcriptomic profiling and provided a comprehensive assessment of genetic responses in drug-resistant organoids. Results: Preliminary results from a limited set of one renal and one colon cancer organoids indicate that the three methods we employed show promise in detecting heterogeneity in drug sensitivity. The use of Elplasia plates allowed for consistent kinetic monitoring of individual organoid survival, and image analysis effectively captured morphological changes associated with varying drug responses. Initial transcriptomic profiling hinted at distinct genetic signatures in drug-resistant organoids, suggesting a potential reflection of physiological heterogeneity seen in patient tumors, potentially including metastatic ones. While these findings are encouraging, further studies with more samples are needed to confirm these observations and refine our approach. Conclusion and Future Directions: Our integrated approach appears to be promising in identifying and characterizing drug sensitivity heterogeneity in CTC-derived cancer organoids. We plan to expand this study to include more patient samples and cancer types, aiming to confirm our findings and identify potential biomarkers of resistance. Citation Format: Yi-chun Han, David Hsieh, Shian-Jiun Shih. Evaluating drug sensitivity heterogeneity in cancer organoids derived from circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B035.
Abstract B009: Caspase-8 mutation promotes head and neck squamous cell carcinoma development and resistance to anti-PD-1
Authors: Zhibin Cui, Liam C Woerner, Steven R Long, Christopher N Peterson, Nathan K VanLandingham, Andrew Nazarenko, Jennifer R Grandis, Daniel E Johnson
Journal: Cancer Research (2025)

Abstract Purpose: Heterozygous mutations in the gene encoding the caspase-8 protease are present in approximately 10% of head and neck squamous cell carcinoma (HNSCC) tumors, where studies indicate they block apoptosis induced by death ligands. However, the role of caspase-8 mutations in HNSCC development in vivo and their influence on response to programmed cell death-1 (PD-1) targeting agents remain unclear. Experimental Design: To investigate the role of caspase-8 mutation in HNSCC, we generated mice with an epithelium-specific, heterozygous knock-in of a representative HNSCC-associated caspase-8 mutation (D305G), regulated by the endogenous caspase-8 promoter. The impact of this mutation was assessed following carcinogen (4-nitroquinoline-1-oxide, 4NQO) treatment in drinking water. Additionally, to evaluate the effects of heterozygous caspase-8 mutations on anti-PD-1 responsiveness, murine HNSCC tumors were established in immunocompetent mice using MOC1 cells engineered to express mutant caspase-8.Results: Mice harboring the D305G caspase-8 mutation developed a higher number of tongue tumors per mouse and showed a greater incidence of advanced invasive carcinomas following 4NQO treatment compared to wild-type caspase-8 controls. In MOC1 tumor models, knockout or heterozygous expression of HNSCC-associated caspase-8 mutants significantly reduced sensitivity to anti-PD-1 therapy, in contrast to tumors derived from parental MOC1 cells. Conclusions: These findings reveal that caspase-8 mutations enhance carcinogen-induced HNSCC progression and confer resistance to anti-PD-1 therapy. Further investigation into caspase-8 mutations as biomarkers for poor immunotherapy response in HNSCC patients is warranted. Citation Format: Zhibin Cui, Liam C Woerner, Steven R Long, Christopher N Peterson, Nathan K VanLandingham, Andrew Nazarenko, Jennifer R Grandis, Daniel E Johnson. Caspase-8 mutation promotes head and neck squamous cell carcinoma development and resistance to anti-PD-1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B009.
Abstract B045: Clustered transcription factor binding reflects transcriptional condensates at cancer super-enhancers and associates with clinical outcome
Authors: Shengyuan Wang, Zhenjia Wang, Chongzhi Zang
Journal: Cancer Research (2025)

Abstract Transcriptional condensates have been shown to play a crucial role in gene regulation and dysregulation in cancer. However, genomic approaches to investigate the links between transcriptional condensates and cancer gene regulation remain underdeveloped. In this study, we employed an integrative computational framework to examine the relationships between genome-wide binding patterns of transcriptional factors (TFs) and potential transcriptional condensates at cancer super-enhancers. We found that TFs with motifs and binding patterns exhibiting a high genomic clustering tendency are significantly associated with super-enhancers. TFs with a high binding clustering tendency also possess high liquid-liquid phase separation abilities. By systematically integrating multi-omics data from TCGA samples with publicly available epigenomics data from cancer cell lines, we found that densely clustered TF binding sites, compared to non-clustered ones, are significantly more enriched at cancer super-enhancers. These clustered sites exhibit higher chromatin accessibility, increased chromatin interactions, and stronger associations with clinical outcomes in breast cancer and colon cancer. Our results suggest that the clustered genomic binding patterns and phase separation properties of TFs collectively contribute to the formation of transcriptional condensates at cancer super-enhancers. This work provides insights for identifying novel biomarkers for cancer diagnosis through biomolecular condensate-inspired genomic approaches. Citation Format: Shengyuan Wang, Zhenjia Wang, Chongzhi Zang. Clustered transcription factor binding reflects transcriptional condensates at cancer super-enhancers and associates with clinical outcome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B045.
Abstract B005: STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis and OXPHOS by targeting HK2 and ATP5a
Authors: Rui Wang
Journal: Cancer Research (2025)

Abstract The evasion of antitumor immunity is a defining characteristic of cancer. STING, a proposed innate immune signaling adapter, plays a crucial role in eliciting antitumor immunity by integrating innate detection and adaptive immune surveillance. STING functions as an intrinsic tumor suppressor but is often downregulated in many human cancer types, and the mechanism by which STING exhibits intrinsic antitumor functions remains unclear. Here, we find that high STING impairs tumor cells growth by inhibiting both aerobic glycolysis and oxidative phosphorylation (OXPHOS) independently of its innate immune action. Knockout of STING in DLBCL cell lines leads to increased mitochondria membrane potential (MMP) and ATP generation, and decreased apoptosis. Mechanistically, STING inhibits hexokinase II (HK2) to obstruct its hexokinase function, and inhibits ATP5a which is a catalytic subunit of the mitochondrial ATP synthase complex responsible for the synthesis of ATP.Consequently, STING inhibits HK2 and ATP5a to limit both tumor aerobic glycolysis and OXPHOS, and enhance antitumor immunity in vivo. This work demonstrates that STING acts as a cell-intrinsic metabolic checkpoint that limits aerobic glycolysis and OXPHOS to exert antitumor functions. These findings hold significant implications for the advancement of STING-based treatment strategies to enhance antitumor immunotherapy. Citation Format: Rui Wang. STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis and OXPHOS by targeting HK2 and ATP5a [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B005.
Abstract B015: Assessment of apoptotic priming in thymic epithelial tumors to define hallmarks of pathogenesis and novel therapeutic strategies
Authors: Christopher Nabel, Yin P. Hung, Brian Do, Xingping Qin, Cameron Fraser, Yolonda Colson, Michael Lanuti, Uma Sachdeva, Cameron Wright, Kris Sarosiek
Journal: Cancer Research (2025)

Abstract The rarity of thymic epithelial tumors and absence of targetable alterations present significant challenges for identifying improved systemic therapies. Recent advances in single-cell sequencing have enhanced our understanding of normal thymus development and the factors underlying malignant transformation. During medullary epithelial differentiation in adulthood, anti-apoptotic factors are expressed, potentially increasing resistance to cell death and thus facilitating tumorigenic processes. We hypothesized that this resistance to apoptotic cell death might be a hallmark of thymic epithelial tumorigenesis and could generate therapeutic vulnerabilities. To investigate this possibility, we measured apoptotic priming and dependencies on anti-apoptotic proteins in metastatic, surgically-resected thymic epithelial tumors. We utilize dynamic BH3 profiling, a functional assay that detects induction of apoptosis in response to titrated doses of pro-apoptotic signals in viable cancer cells freshly isolated from resection specimens. Our interim results show that advanced, WHO B-subtype thymomas are highly primed for apoptotic cell death, even in chemotherapy-resistant tumors, supporting the notion that thymomas may be more radiosensitive than chemosensitive. Furthermore, we find that thymomas consistently exhibit dependence on anti-apoptotic proteins, which may be targeted by recently-developed BH3 mimetics that inhibit these proteins. Apoptotic priming and dependencies are further enhanced by co-treated with clinically-relevant, targeted anti-cancer agents. To understand the basis for these findings, we evaluate the role of apoptotic priming during normal thymic epithelial development to determine how apoptotic resistance aligns with other molecular features of medullary epithelial biology, including the transcription of non-thymic tissue antigens and DNA damage response. These findings have significant therapeutic implications for further clinical investigation and deepen the foundational knowledge of molecular factors contributing to tumorigenesis, revealing new opportunities for preclinical modeling. Citation Format: Christopher Nabel, Yin P. Hung, Brian Do, Xingping Qin, Cameron Fraser, Yolonda Colson, Michael Lanuti, Uma Sachdeva, Cameron Wright, Kris Sarosiek. Assessment of apoptotic priming in thymic epithelial tumors to define hallmarks of pathogenesis and novel therapeutic strategies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B015.
Abstract A007: Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma
Authors: Elizabeth G Fernandez, Wilson X Mai, Kai Song, Nicholas A Bayley, Andrew J. Souers, Jingyi Jessica Li, Thomas G. Graeber, Timothy F Cloughesy, David A. Nathanson
Journal: Cancer Research (2025)

Abstract Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death. Citation Format: Elizabeth G Fernandez, Wilson X Mai, Kai Song, Nicholas A Bayley, Andrew J. Souers, Jingyi Jessica Li, Thomas G. Graeber, Timothy F Cloughesy, David A. Nathanson. Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A007.
Abstract A011: ATM inhibitors exploit checkpoint defects and ATM-dependent double strand break repair to induce mitotic cell death in TP53-mutant glioblastoma
Authors: Daniel J Laverty, Shiv Gupta, Gary Bradshaw, Jiajia Chen, Brett L Carlson, Nery Matias Calmo, Shulan Tian, Jann N Sarkaria, Zachary D Nagel
Journal: Cancer Research (2025)

Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ) and show that HR and MMEJ are therapeutically-targetable treatment resistance mechanisms in glioblastoma. Using a targeted screen of clinically relevant small molecules, we identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor. Mechanistic studies in GBM cell lines show that AZD1390 suppresses DSB end resection and blocks radiation-induced phosphorylation of DSBR proteins including nibrin, Rad50, and Mettl16. Interestingly, AZD1390 enhances the cytotoxic effects of TMZ and radiation in both treatment-naïve and treatment-resistant GBM samples harboring mutations in the TP53 gene. We show that TP53 mutation is associated with upregulation of ATM pathway genes in GBM patient samples along with heightened ATM-dependent HR and MMEJ in GBM cell lines. Finally, we show that TP53-mutant GBMs fail to arrest in G2 phase after radiation/AZD1390 or TMZ/AZD1390 combinations and instead attempt mitosis, leading to mitotic cell death. Expression of the mitotic DSBR factor, RHINO1, is associated with poor prognosis in patients with TP53-mutant GBMs, suggesting that factors that promote efficient mitotic DSBR protect TP53-mutant GBMs from treatment-induced cell death. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes ATM inhibition as a potential strategy for overcoming intrinsic and acquired treatment resistance in TP53-mutant GBMs. Citation Format: Daniel J Laverty, Shiv Gupta, Gary Bradshaw, Jiajia Chen, Brett L Carlson, Nery Matias Calmo, Shulan Tian, Jann N Sarkaria, Zachary D Nagel. ATM inhibitors exploit checkpoint defects and ATM-dependent double strand break repair to induce mitotic cell death in TP53-mutant glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A011.