tbuckley/cabot-search huggingface dataset:
Abstract 7060: Mitochondrial metabolism and racial disparity of bladder cancer
Authors: Karthik Reddy Kami Reddy, Jun Hyoung Park, Roni J. Bollag, Martha K. Terris, Seth P. Lerner, Minhaj Siddiqui, Yair Lotan, Jianjun Gao, Benny Abraham Kaipparettu, Nagireddy Putluri
Journal: Cancer Research (2024)

Abstract Bladder cancer mortality is significantly higher in African American patients compared to their European American counterparts. This inferior survival of African American cancer patients is driven at least in part by distinctive intrinsic tumor biology, more specifically altered metabolic activity. However, underlying molecular mechanism for the African American bladder cancer mortality are largely unexplored. Our pioneering metabolomic findings demonstrate alterations in metabolic pathways between African American and European American bladder cancer, specifically those involved in driving energy metabolism. Along these line, we observed increased electron transport chain activity and ATP production in African American bladder cancer could be a result of distinctive rewiring of energy metabolism compared to their European American counterparts. We further performed gene set enrichment analysis by mapping metabolites to genes and observed that oxidative phosphorylation pathway was uniquely enriched in African American tumors compared to European American tumors. In addition, from in vitro assays, mitochondrial complex protein and activity were altered in African American bladder cancer. To determine the role of glutamine mediated increased electron transport chain activity and ATP production in African American bladder cancer, we evaluated the metabolic flux using 13C labeled tracers in both African American and European American bladder cancer cell lines. Metabolic flux analysis revealed that African American cell lines are more glutamine dependent and that producing increased tricarboxylic acid intermediates. Overall, our data indicate that elevated mitochondrial metabolism and oxidative phosphorylation driven by enhanced glutaminolysis may facilitate African American bladder cancer progression. These findings provide the rationale to use mitochondrial-specific inhibitors to target at least a subset of African American bladder cancer patients. Citation Format: Karthik Reddy Kami Reddy, Jun Hyoung Park, Roni J. Bollag, Martha K. Terris, Seth P. Lerner, Minhaj Siddiqui, Yair Lotan, Jianjun Gao, Benny Abraham Kaipparettu, Nagireddy Putluri. Mitochondrial metabolism and racial disparity of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7060.
Abstract 459: Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis
Authors: Sui-Chih Tien, Chin-Chun Chang, I-Chih Chen, Ching-Hsuan Huang, Hsuan-Yu Peng, Yu-Ting Chang, Ming-Chu Chang, Chun-Mei Hu, Wen-Hwa Lee
Journal: Cancer Research (2024)

Abstract Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia, which is associated with reduced survival, decreased quality of life, and higher rates of metastatic disease. To date, the diagnostic and therapeutic options of PDAC-associated cachexia remain limited due to the lack of a complete understanding of the underlying pathological mechanism. Here, we demonstrate that fat loss is the earliest feature of cachexia induced by PDAC through its secreted exosomes. By analyzing exosomal components of normal and cancer-derived exosomes through small RNA-seq, we identify miR-16-5p, miR-21-5p, miR-29a-3p and miR-125b-5p enriched in pancreatic cancer-derived exosomes and in the exosomes from sera of mice or patients with pancreatic tumor. Among these, miR-16-5p and miR-29a-3p play a key role in fat loss by inhibiting adipogenesis through decreasing Erlin2 and CMPK1 expression leading to C/EBPβ and PPARγ downregulation. Synergistically, miR-29a-3p increases ATGL expression to facilitate lipolysis by suppressing MCT1 expression. Furthermore, PDAC-derived exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss, suggesting that these two exosomal miRs are required for PDAC-induced fat loss. These findings unravel a precise mechanism of how PDAC causes adipose atrophy via exosomal miRs and may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia. Citation Format: Sui-Chih Tien, Chin-Chun Chang, I-Chih Chen, Ching-Hsuan Huang, Hsuan-Yu Peng, Yu-Ting Chang, Ming-Chu Chang, Chun-Mei Hu, Wen-Hwa Lee. Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 459.
Abstract 7021: Selecting your epigenomic assay: Comparing ChIP-seq, CUT&amp;RUN, and CUT&amp;Tag
Authors: Angela H. Guo, Christopher R. Comeau, Fang Chen
Journal: Cancer Research (2024)

Abstract For many years, chromatin immunoprecipitation (ChIP) was the standard assay for studying epigenetic mechanisms. However, two new versatile techniques have recently been developed that are faster, experimentally easier, and more cost-effective than ChIP. Cleavage Under Targets &amp; Release Using Nuclease (CUT&amp;RUN) and Cleavage Under Targets &amp; Tagmentation (CUT&amp;Tag) can be used for understanding protein-DNA interactions within the natural chromatin context of the cell. Both CUT&amp;RUN and CUT&amp;Tag can be combined with Next Generation Sequencing (NGS) to analyze the function of histone modifications and the binding of transcription factors, DNA replication factors, or DNA repair proteins across the genome. CUT&amp;RUN and CUT&amp;Tag are rapid, robust, and true low cell number methods for the detection of protein-DNA interactions. Unlike ChIP, both assays are free of formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation. When compared to ChIP, CUT&amp;RUN and CUT&amp;Tag require fewer starting cells (as low as 5,000 – 20,000), are shorter assays (one day from cells to DNA), and generate lower background signal (requiring fewer sequencing reads). At Cell Signaling Technology (CST), we have developed ChIP-seq, CUT&amp;RUN, and CUT&amp;Tag assay kits and validated a broad set of antibodies against histone modifications, transcription factors, and cofactors that are compatible with these kits. This poster will discuss the fundamentals of all three assays and highlight important factors to consider when selecting an assay for your experiment. Through our antibody validation efforts, we have also generated a unique and extensive archive of ChIP-seq, CUT&amp;RUN, and CUT&amp;Tag NGS data using recombinant, monoclonal antibodies. This allows for the controlled comparison of these three commonly used chromatin profiling techniques. In this poster, I will highlight the similarities and differences between these assays when mapping a variety of histone modifications, transcription factors, and cofactor binding events across multiple sample types. Citation Format: Angela H. Guo, Christopher R. Comeau, Fang Chen. Selecting your epigenomic assay: Comparing ChIP-seq, CUT&amp;RUN, and CUT&amp;Tag [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7021.
Abstract 7046: Proteogenomic and immunologic profiles of head and neck cancer patients of African ancestry
Authors: Fan Yang, Fanghui Chen, Chloe Shay, Nabil F. Saba, Yong Teng
Journal: Cancer Research (2024)

Abstract Blacks/African Americans (BAAs) with head and neck squamous cell carcinoma (HNSCC) have worse survival than Whites. However, the complex molecular biomarkers and signatures of HNSCC among BAAs and molecular distinction associated with HNSCC disparities are largely unknown. Here we show the results of a multi-omics analysis of 500 patients (48 BAAs and 452 Whites). Comparative analyses between the racial groups were performed at the level of genomics, pathways, molecular subtype, tumor immune infiltration, protein alterations and prognosis. We found that overall survival in BAAs with HPV-unrelated HNSCC is significantly shorter than in White patients. Ancestry-related differential mutation spectrum, DNA methylation, gene and protein expression pattern and immune infiltration landscape were identified. Particularly, FAT1 mutation is significantly associated with its gene expression in BAA HNSCC and poor overall survival in this group. In BAA HNSCC, SALL3 gene expression is positively associated with its gene CNVs, while RTP4 gene expression is inversely correlated with its methylation. High EGFR_pY1068 and RAD50 levels correlate with poor prognosis in BAAs with HNSCC. The immune infiltration enrichment scores of Th17 cells, activated dendritic cells, monocytes and neutrophils in BAA HNSCC were significantly lower than those in White HNSCC. By combining multi-omics analysis and data validation using in-house-made tumor tissue arrays, this study comprehensively elucidates the genetic landscape, immune response, and tumor biology in BAA and White HNSCC patients, providing a molecular basis for future research in identifying appropriate screening modalities and therapeutic interventions leading to improved outcomes in BAAs with HNSCC. Citation Format: Fan Yang, Fanghui Chen, Chloe Shay, Nabil F. Saba, Yong Teng. Proteogenomic and immunologic profiles of head and neck cancer patients of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7046.
Abstract 1147: Sub-cellular spatial resolution of immune and stromal interactions underlying prostate cancer progression
Authors: Chia-Kuei Mo, Reyka G. Jayasinghe, Ateih Abedin do, Xiang Li, Cody Weimholt, Eric H. Kim, Russell Pachynski, Feng Chen, Li Ding
Journal: Cancer Research (2024)

Abstract Prostate cancer boasts a complex morphological structure and diverse cellular composition, yet current technology falls short in resolving the detailed spatial interactions among cells within the environment. In this study, we employed the Xenium platform, coupled with the 3D reconstruction tool Mushroom, to examine high-resolution spatial cellular interactions within the prostate cancer microenvironment. Our investigation focused on the transition of molecular characteristics from normal to high-grade prostatic intraepithelial neoplasia (HGPIN, pre-cancer), spanning the spectrum of Gleason Grades 3 to 4 and advancing to metastatic prostate cancer. We identified genes with unique spatial and grade-dependent expression profiles, including MYC, CP, and UHCL1. Evaluating sub-cellular imaging facilitated a comprehensive characterization and quantification of immune and stromal interactions, unveiling distinct spatial niches across transition stages. These findings underscore the nuanced immune interactions within the tumor microenvironment and offer crucial insights into the development of immunotherapeutic approaches tailored to the specific spatial and immune dynamics observed in advanced prostate cancer. This research contributes to the evolving understanding of prostate cancer progression, providing a foundation for the development of targeted therapies that disrupt specific cellular interactions. Citation Format: Chia-Kuei Mo, Reyka G. Jayasinghe, Ateih Abedin do, Xiang Li, Cody Weimholt, Eric H. Kim, Russell Pachynski, Feng Chen, Li Ding. Sub-cellular spatial resolution of immune and stromal interactions underlying prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1147.
Abstract 4563: Ferroptotic mechanism of drug induced toxicity of PARPi and AurKi in prostate cancer
Authors: August John, Kuntian Luo, Zhenkun Lou, Liewei Wang
Journal: Cancer Research (2024)

Abstract BACKGROUND: Cancer is typically treated with a combination of drugs rather than monotherapy stratagems, but identification of synergistic drug combinations for the treatment of cancers is challenging. Here we present the combination of PARP and Aurora Kinase inhibitors synergize through induction of the ferroptosis pathway of cell death. METHODS: We identified these drugs through an unbiased screen of enriched drug class response correlations. We then validated a synergistic cell killing effect of multiple drugs of each class by in vitro drug screening. Next, we performed reversal experiments using a ferroptosis inhibitor and lipid peroxide staining to confirm ferroptosis is a relevant cell death pathway. We performed Western immunoblot analysis in cells overexpressing putative Aurora Kinase phospho-substrates in the relevant pathway of interest, and performed site directed mutagenesis experiments to show the relevant amino acid altered by kinase activity. We also performed a series of qPCR and co-IP experiments to show PARPi effect on the antioxidant signaling pathway. RESULTS: We validated and identified synergy in a prostate cancer specific context. Next, we found Talazoparib and Alisertib induced ferroptosis after synergy was reduced with a ferroptosis inhibitor and lipid peroxides increased accumulation. We found a novel mechanism action for Alisertib, wherein Aurora Kinase inhibitors can alter the phospho-status and activity of the iron reduction enzyme Steap3.We also found that PARP inhibitors can affect the Nrf2-driven antioxidant signaling pathway on a transcriptional level. CONCLUSION: Aurora Kinase inhibitors and PARP inhibitors for the treatment of prostate cancer was identified and was validated as synergistic, which revealed new functional roles of both drugs in the context of cell killing. These findings represent a new clinical combination of drugs in prostate cancer and reveal a novel role for this drug class in ferroptosis. Citation Format: August John, Kuntian Luo, Zhenkun Lou, Liewei Wang. Ferroptotic mechanism of drug induced toxicity of PARPi and AurKi in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4563.
Abstract 1115: Enhancing lung cancer sensitivity to chemotherapy, radiation, and chemo-radiation through inhibition of a mitotic checkpoint kinase BUB1
Authors: Shivani Thoidingjam, Sushmitha Sriramulu, Stephen L. Brown, Farzan Siddiqui, Benjamin Movsas, Shirish Gadgeel, Shyam Nyati
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) represent two major subtypes of lung cancer, marked by challenging treatment resistance. Our study explores the inhibition of BUB1, a critical mitotic checkpoint kinase, in conjunction with radiotherapy and chemotherapy. This approach has the potential to overcome resistance, thus enhancing the efficacy of treatment and improving treatment outcomes for lung cancer patients. We analyzed BUB1 expression in lung cancer using TCGA datasets and patient tissue microarrays (TMAs). In vitro experiments used four NSCLC and two SCLC cell lines with BUB1 inhibitor (BAY1816032), Paclitaxel, Cisplatin and Olaparib. Cells were irradiated (2, 4, or 6 Gy), and assays measured proliferation, long-term effects, DNA damage, and repair. Bioinformatic analysis in NSCLC subtype, lung adenocarcinoma (LUAD) demonstrated marked overexpression of BUB1, correlated with cancer stage, tumor grade and survival. Lung cancer TMAs revealed elevated expression of BUB1 protein in SCLC that correlated with poorer survival. BUB1 inhibition (BUB1i) induced cytotoxicity in LUAD cell lines at micromolar concentrations, while nanomolar concentrations enhanced cell death significantly when combined with radiation. Furthermore, BUB1i sensitized LUAD cells to different classes of chemotherapy (Paclitaxel, Cisplatin), and PARP inhibitor (Olaparib) alone (chemo-sensitization) or with radiation therapy (chemo-radiosensitization). H2030 and H1975 demonstrated higher chemo-radiosensitization efficacy compared to A549, likely due to genetic differences, potentially including a p53 mutation that improves sensitivity by affecting DNA repair and cell cycle regulation. Preliminary investigations revealed DNA double-strand breaks, indicated by prolonged γH2AX foci, and the inhibition of the NHEJ DNA damage repair pathway after BUB1 ablation. Among SCLC cell lines, NCI-H1876 demonstrated higher radiosensitivity upon BUB1 ablation compared to NCI-H2198, potentially due to genetic differences/mutations affecting radiation response. The study highlights the potential of BUB1i in enhancing the sensitivity of NSCLC and SCLC cells to radiotherapy and chemotherapy and provide rationale to explore BUB1i as a novel approach to enhance lung cancer therapy in clinical trials. Citation Format: Shivani Thoidingjam, Sushmitha Sriramulu, Stephen L. Brown, Farzan Siddiqui, Benjamin Movsas, Shirish Gadgeel, Shyam Nyati. Enhancing lung cancer sensitivity to chemotherapy, radiation, and chemo-radiation through inhibition of a mitotic checkpoint kinase BUB1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1115.
Abstract 249: Deciphering the impact of TRIB3-ELF4 interaction in regulating CDK6 on cancer stem cell activity in endometrial cancer
Authors: Wen-Ling Wang, Wen-Wei Chang
Journal: Cancer Research (2024)

Abstract Background: Endometrial cancer (EC) is the most common gynecological tumor among women worldwide, posing a serious threat to women's health. ELF4 (E74 like ETS transcription factor 4), a member of the ETS family, plays a role in facilitating cancer progression. Our previous work demonstrated the role of direct binding between ELF4 and tribbles pseudokinase 3 (TRIB3) in promoting β-catenin expression. In this study, we further explore ELF4's involvement in the maintenance of cancer stem cells (CSCs) in EC. Methods: The vital role of ELF4 in EC was determined through gain- and loss-of-function assays. ELF4 was silenced in two EC cell lines, AN3CA and HEC-1A, and primary EC cells from a Taiwanese patient (EMC6), using RNA interference techniques. The expression of ELF4, TRIB3, and CDK6 in human EC samples was assessed using immunohistochemistry. Tumorsphere formation assays, quantitative real-time PCR, and immunoblotting quantified CSC activity and the involvement of related signaling pathways. Transcriptional regulation associated with ELF4 was investigated using luciferase reporter assays and chromatin immunoprecipitation. Results: Analysis of the TCGA database via the TISIDB web tool revealed that elevated ELF4 levels correlated with higher histological grades, advanced clinical stages, and poorer overall survival in EC patients. A grade-dependent increase in ELF4 expression was observed using tissue microarrays. Knockdown of ELF4 in EC cell lines and patient-derived EC cells significantly reduced cell proliferation, cell cycle progression, migration, invasion, and CSC activity. RNA-seq data analysis of ELF4-knockdown EC cells identified CDK6 as a potential downstream target of the ELF4/TRIB3 interaction. Knockdown of ELF4 and TRIB3 significantly downregulated CDK6 expression. Co-expression of TRIB3 and ELF4 enhanced CDK6 expression, and their expression was positively associated with CDK6 in EC specimens. We also demonstrated that CDK6 facilitates EC-CSC activity. Knockdown of CDK6 significantly attenuated tumorsphere formation and reduced the levels of cancer stemness-related proteins, including OCT4, NANOG, and c-MYC. Conclusion: Our study demonstrates the essential roles of ELF4 and TRIB3 in regulating CDK6 expression, contributing to the maintenance of EC-CSCs. Citation Format: Wen-Ling Wang, Wen-Wei Chang. Deciphering the impact of TRIB3-ELF4 interaction in regulating CDK6 on cancer stem cell activity in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 249.
Abstract 4573: Pre-clinical evaluation of small molecule CHK2 inhibitor, ART446, pre-IND candidate that enhances the olaparib and irinotecan
Authors: Taegon Baik, Young Woo Kang, Ha Young Lee, Jin Whan Kim, A Hyeon Jeong, Jong Oh Kim, Woo-Young Kim
Journal: Cancer Research (2024)

Abstract Background: Poly (ADP-ribose) polymerase (PARP) plays a pivotal role in DNA damage repair. Tumors with DNA Damage Response (DDR) defects exhibit increased susceptibility to drugs targeting PARP. The drugs induce DNA damage like Irinotecan (a Topoisomerase I inhibitor) are widely used in clinic as well. However, intrinsic resistance remains a significant obstacle, leading to frequent treatment failures. Chk2 is activated in response to these DNA damage inducing agents and hold the cell cycle. We developed pre-IND candidate ART446, with the aim of exploring its therapeutic potential in sensitizing DNA damage-targeting reagents. Results: In the radiometric HopSpot Kinase Assay, ART446 demonstrated significant inhibition of Chk2 (IC50, 9 nM). In HT-29 colon adenocarcinomas, co-treatment with SN38 and ART446 exhibited a synergistic therapeutic effect in vitro, with a subsequent in vivo tumor growth assay demonstrating a remarkable combined effect (TGI; Irinotecan, 46%; ART446, 16%; combined, 83.4%). Further extending our investigation to triple-negative breast adenocarcinoma MDA-MB-436, characterized by a BRCA1 mutation, we explored the sensitization potential of ART446 to PARP inhibitors. Strikingly, the combination therapy with a PARP inhibitor, Olaparib surpassed monotherapy outcomes, resulting in complete tumor growth inhibition (TGI: Olaparib, 73%; ART446, 20%; combined, 102%). Mechanistic insights revealed an increase in gamma H2AX levels by ART446 and a decrease in active forms of Chk2 which were activated by Olaparib affirming that Olaparib-induced Chk2 inhibition contributed to the sensitization effect. Conclusions: The pre-IND candidate ART446 exhibits promising potential in enhancing the therapeutic effects of Olaparib and Irinotecan. These findings provide a robust foundation for further clinical development, offering a strategic approach to overcome resistance in cancer treatment. Citation Format: Taegon Baik, Young Woo Kang, Ha Young Lee, Jin Whan Kim, A Hyeon Jeong, Jong Oh Kim, Woo-Young Kim. Pre-clinical evaluation of small molecule CHK2 inhibitor, ART446, pre-IND candidate that enhances the olaparib and irinotecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4573.