tbuckley/cabot-search huggingface dataset:
Abstract 5240: Effective inhibition of TMPRSS2-ERG positive prostate cancer cells by a new formula of ERGi-USU-6
Authors: Binil Eldhose, Charles P. Xavier, Mallesh Pandrala, Sanjay V. Malhotra, Albert Dobi
Journal: Cancer Research (2020)

Abstract Background: Prostatic adenocarcinoma is among the leading cause of cancer-related deaths among men in the United States. The Erythroblast Transformation-Specific-Related Gene, ERG is dormant in normal prostate epithelium. Due to gene fusions, the ERG oncogene is frequently activated by androgenic signals in prostate cancer. ERG disrupts the normal differentiation, promotes epithelial-mesenchymal transition, migratory and invasive properties of cancer cells. Approximately 35% of metastatic castration-resistant prostate cancers harbor ERG oncogene. Due to the failure of androgen axis directed therapies, there is an urgent need to develop inhibitors to targeting prostate cancer-causing genes, such as ERG. We have identified a potent small-molecule inhibitor ERGi-USU that is remarkably selective for inhibiting the growth of ERG positive cancer cells through direct binding to the RIOK2 atypical kinase, a putative upstream regulator of ERG. We completed a structure-activity relationship (SAR) study and compound development resulting in the potent derivative, ERGi-USU-6. Our current objective is to improve the therapeutic properties of ERGi-USU-6, by new salt formulations. Methods: Evaluation of the five selected salt formulations of ERGi-USU-6 were performed by assessing the growth of ERG positive prostate cancer cell line (VCaP) and by monitoring ERG and RIOK2 protein levels. Selectivity was assessed by monitoring the growth, endogenous ERG and RIOK2 levels in normal ERG positive human umbilical vein derived endothelial cells (HUVEC). The IC50 values for cell growth, compared to the parental compound were calculated in a 12-step dilution range performed in triplicates and independently repeated three times. Cell growth was measured by quantitative Cell Glow assay monitoring viable cells using Perkin Elmer Envision assay instrument and protein levels were quantified by measuring bioluminescence in IBright instrument in a wide dynamic range. Results: One new salt formula with improved activity were identified, demonstrating improved cell growth (IC50=89nM vs. parental IC50=139), ERG protein and RIOK2 protein inhibition. None of the salt formulas of ERGi-USU-6 showed any effect on the primary cultures of the ERG positive normal endothelial cells (HUVEC) in the effective concentration range. Conclusion: The first evaluation of salt formulas of ERGi-USU-6 may open the possibilities for preclinical assessments of this remarkably cancer-selective compound. Citation Format: Binil Eldhose, Charles P. Xavier, Mallesh Pandrala, Sanjay V. Malhotra, Albert Dobi. Effective inhibition of TMPRSS2-ERG positive prostate cancer cells by a new formula of ERGi-USU-6 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5240.
Abstract 6321: BEND3 modulates sensitivity to the UBA1 inhibitor TAK-243 by regulating expression of the multidrug transporter BCRP
Authors: Samir H. Barghout, Ahmed Aman, Zachary Blatman, Karen Arevalo, Geethu Thomas, Neil MacLean, Xiaoming Wang, Rose Hurren, Troy Ketela, Moustafa Abohawya, Taira Kiyota, Rima Al-Awar, Aaron D. Schimmer
Journal: Cancer Research (2020)

Abstract TAK-243 (MLN7243) is a first-in-class inhibitor of the ubiquitin-activating enzyme (UBA1) that catalyzes the first step in the ubiquitylation cascade whereby proteins are tagged with mono- or poly-ubiquitin to induce their degradation or modify their functions. Based on its preclinical efficacy and tolerability, TAK-243 has entered phase 1 clinical trials in advanced malignancies. However, the determinants of sensitivity to TAK-243 remain largely unknown. Therefore, we conducted a positive-selection, genome-wide CRISPR/Cas9 knockout screen in OCI-AML2 cells followed by selection with lethal TAK-243 concentrations to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout conferred resistance to TAK-243 (FDR = 0.0012). BEND3-targeting gRNAs were enriched up to 10,000-fold after selection with the drug. To validate the screen results, we independently knocked out BEND3 in OCI-AML2 cells and confirmed the resistance phenotype. In vivo, tumors of BEND3-knockout cells were resistant to TAK243 (20 mg/kg twice weekly) as opposed to control tumors that showed dramatic reductions in tumor growth rate. As assessed by immunoblotting, BEND3 knockout dampened TAK-243 effects on ubiquitylation, proteotoxic stress and DNA damage response. Mechanistically, BEND3 knockout upregulated the ABC efflux transporter breast cancer resistance protein (BCRP; ABCG2), and decreased intracellular levels of TAK-243. It also conferred partial cross-resistance to pevonedistat and TAK-981–related selective inhibitors of the NEDD8-activating enzyme (NAE) and the SUMO-activating enzyme (SAE), respectively, as well as known substrates of BCRP (mitoxantrone and doxorubicin). Finally, TAK-243 sensitivity strongly correlated with BCRP expression in a panel of 30 cancer cell lines of different origin, and chemical inhibition of BCRP but not P-gp sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity. Citation Format: Samir H. Barghout, Ahmed Aman, Zachary Blatman, Karen Arevalo, Geethu Thomas, Neil MacLean, Xiaoming Wang, Rose Hurren, Troy Ketela, Moustafa Abohawya, Taira Kiyota, Rima Al-Awar, Aaron D. Schimmer. BEND3 modulates sensitivity to the UBA1 inhibitor TAK-243 by regulating expression of the multidrug transporter BCRP [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6321.
Abstract 2557: 15-lipoxygenase-1 suppresses linoleic acid promotion of colorectal tumorigenesis through oxidative metabolism of PI3P_linoleic acid to inhibit membranous LRP5 recycling and WNT/β-catenin signaling activation
Authors: Fuyao Liu, Xiangsheng Zuo, Yi Liu, Yasunori Deguchi, Micheline J. Moussalli, Weidong Chen, Peiying Yang, Bo Wei, Lin Tan, Philip L. Lorenzi, Shen Gao, Jonathan C. Jaoude, Amir Mehdizadeh, Lovie A. Valentin, Daoyan Wei, Imad Shureiqi
Journal: Cancer Research (2020)

Abstract Western-type diets have been increasingly enriched with linoleic acid (LA). The impact of excess dietary LA on cancer risk remains poorly understood although some studies suggest that high LA diets promote chemically-induced colorectal carcinogenesis (CRC) in rodent models. 15-lipoxygenase-1 (15-LOX-1), the main metabolizing enzyme of LA, is transcriptionally silenced during the early stages of CRC. Whether 15-LOX-1 impacts the effects of excess LA on CRC is unknown. Herein, we report that high dietary LA promoted CRC in intestinally targeted APC mutation (ApcΔ580) and azoxymethane-induced CRC mouse models by upregulating expression of LRP5, a Wnt receptor, and aberrant β-catenin activation. These effects were negatively regulated by 15-LOX-1 when this enzyme was transgenically expressed in intestinal epithelial cells. Complementary genetic deletion studies of 15-LOX-1 in mice further supported 15-LOX-1's suppressive effects on these events. Mechanistic studies showed that 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17 and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time the importance of linoleic acid metabolism by 15-LOX-1 within complex lipids such as PI3P in regulating LRP5 membranous abundance and subsequently Wnt/β-catenin aberrant signaling activation and CRC risk. These results strongly support the need to carefully consider the potential of increasing CRC risk by enriching the diets with LA especially for individuals with low 15-LOX-1 expression. Citation Format: Fuyao Liu, Xiangsheng Zuo, Yi Liu, Yasunori Deguchi, Micheline J. Moussalli, Weidong Chen, Peiying Yang, Bo Wei, Lin Tan, Philip L. Lorenzi, Shen Gao, Jonathan C. Jaoude, Amir Mehdizadeh, Lovie A. Valentin, Daoyan Wei, Imad Shureiqi. 15-lipoxygenase-1 suppresses linoleic acid promotion of colorectal tumorigenesis through oxidative metabolism of PI3P_linoleic acid to inhibit membranous LRP5 recycling and WNT/β-catenin signaling activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2557.
Abstract 4654: Supplemental one-carbon metabolism related B vitamins and lung cancer risk in the Women's Health Initiative
Authors: Theodore M. Brasky, Roberta M. Ray, Sandi L. Navarro, Jeannette M. Schenk, Alison M. Newton, Marian L. Neuhouser
Journal: Cancer Research (2020)

Abstract We and others have reported associations between B vitamins principally involved in one-carbon metabolism and increased lung cancer risk; however results for women have been inconsistent. Here we report on the association of supplemental vitamins B6, folic acid, and B12 intake and lung cancer risk using data from the Women's Health Initiative (WHI) study of postmenopausal women. Between 1993 and 1998, 161,808 women were recruited to participate in the WHI at 40 US clinical centers. After exclusions, 159,232 women were available for analysis and followed prospectively for 18.3 years. Among them, 3,836 incident lung cancer cases were diagnosed. At baseline, supplemental B vitamins from multivitamins, vitamin mixtures, and individual supplements were assessed. Adjusted Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between supplemental B vitamin intake and lung cancer risk. Relative to non-users, women who took ≥50 mg/d of vitamin B6 had 18% (HR 0.82, 95% CI: 0.70-0.97) reduced lung cancer risk. Associations did not differ significantly by smoking status or lung cancer histology. Intakes of folic acid and vitamin B12 were not associated with risk. There is a need for replication of our findings from large, prospective studies with high-quality measurement of supplement intakes. As such, no recommendation can be made at present on the use of B6 supplements for lung cancer prevention in women. Citation Format: Theodore M. Brasky, Roberta M. Ray, Sandi L. Navarro, Jeannette M. Schenk, Alison M. Newton, Marian L. Neuhouser. Supplemental one-carbon metabolism related B vitamins and lung cancer risk in the Women's Health Initiative [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4654.
Abstract 1027: Inhibition of c-MET upregulates PD-L1 related immune escape in lung adenocarcinoma
Authors: Xian Sun, Chia-Wei Li, Wei-Jan Wang, Mien-Chie Hung
Journal: Cancer Research (2020)

Abstract Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in phase III clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Tivantinib upregulates PD-L1 in NSCLC cells in dose and time-dependent manner. Mechanistically, inhibition of c-MET suppresses p-GSK3-beta, leading to the stabilization of PD-L1. Collectively, our findings suggest a potential crosstalk between c-Met inhibition and immune escape and provide a rationale for the combination therapy of c-Met inhibitors and immune checkpoint blockade in NSCLC. Citation Format: Xian Sun, Chia-Wei Li, Wei-Jan Wang, Mien-Chie Hung. Inhibition of c-MET upregulates PD-L1 related immune escape in lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1027.
Abstract 2998: Linear confined space migration induces treatment resistance and gene expression changes in glioblastoma multiforme
Authors: Anish Babu, Patrick McKernan, Xue Cai, James Battiste
Journal: Cancer Research (2020)

Abstract Background: Glioblastoma Multiforme (GBM), an aggressive brain cancer, is known for its treatment resistant recurrence and lethality. The diffuse migration and invasion of GBM cells commonly occurs along brain white matter tracts in linear confined spaces between axons and has significant clinical implications as these cells survive initial therapies forming the main source of recurrent tumors resistant to therapies. In this context, this project aims to analyze the treatment resistance mechanism associated with linear confined space migrating cells (LCSM) to devise a better treatment strategy for GBM. Methods: We used a combination of microfluidic technology (5 µM wide channels in PDMS block) emulating linear white matter tracts in brain and standard molecular analysis (confocal microscopy, high content imaging, western blot, and flow cytometry) to investigate LCSM cells compared to Standard Monolayer Culture cells (SMCs) for the mechanism of drug resistance. Both established and patient derived GBM cell lines were used in the study. Results: LCSM cells were more resistant to chemo-drugs (Temozolomide and Doxorubicin) than SMCs as observed in cell viability assays. Enhanced drug efflux was observed in LCSM cells compared to SMC cells indicating the activation of drug efflux pumps. Protein expression analysis indicated that ABC drug efflux transporters (ABCB1, ABCC1, ABCG2) were activated or enhanced at varying levels in different LCSM cells compared to SMCs. Pharmacological inhibition of the prominently expressed ABCG2 protein using KO143 resulted in enhanced cell death by chemo drugs, suggesting that chemo resistance in LCSM, at least in part, is conferred by ABCG2 or other efflux transporters. In addition, CD133 (a marker of treatment resistant stem cell population in GBM) and AQP4 (Aquaporin 4; pro-migratory marker in GBM) were also enhanced in LCSM compared to SMC suggesting their possible roles in treatment resistance. Conclusion: Preliminary studies reveal that the enhanced expression ABC transporters, prominently ABCG2, might be responsible for enhanced drug efflux and low therapeutic sensitivity in GBM- LCSM cells. The over expression of AQP4 and CD133, and differential expression of other genes suggest that more complex mechanisms might be involved, which are currently under investigation. Citation Format: Anish Babu, Patrick McKernan, Xue Cai, James Battiste. Linear confined space migration induces treatment resistance and gene expression changes in glioblastoma multiforme [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2998.
Abstract 3702: A lineage-specific lncRNA driven by Foxa1 associated super enhancer promotes tumor growth through interacting YBX1
Authors: Yin Zhang, Yong-xin Huang, Dan-lan Wang, Hai-yan Yan, Yin Dong
Journal: Cancer Research (2020)

Abstract Lineage-specific expression of genes plays important roles in tumorigenesis. It has been suggested that lncRNAs tend to be more lineage-specifically expressed than protein-coding genes. However, the regulation and role of lineage-specific lncRNAs remains largely unknown. In this study, we reported a lncRNA DSCAM-AS1 that specifically expressed in lung adenocarcinoma and luminal breast cancer. The expression of DSCAM-AS1 was regulated by two super enhancer clusters driven by Foxa1. Foxa1 can directly bind to promoter of DSCAM-AS1. In breast cancer, DSCAM-AS1 was also transcriptionally regulated by ERα, which formed complex with Foxa1. Higher expression of DSCAM-AS1 was associated with poor poor prognosis in both lung adenocarcinoma and luminal breast cancer patients. Silencing or knock-out of DSCAM-AS1 significantly reduce the growth of lung adenocarcinoma and luminal breast cancer cells. We observed silencing or knock-out of DSCAM-AS1 could reduce the expression of Foxa1 in lung adenocarcinoma and breast cancer cells. We also found a significant decrease of ERα expression after silencing or knock-out of DSCAM-AS1 in luminal breast cancer cells. Mechanistically, we found DSCAM-AS1 could interact with YBX1 and enhance recruitment of YBX1 at the promoter region of Foxa1 and ERα. DSCAM-AS1 could form a positive feedback loop with Foxa1 and ERα. Our findings may provide another regulatory loop: Foxa1 and ERα drive expression of super enhancer associated lncRNA DSCAM-AS1 and form a positive feedback loop with it, which play important roles in maintaining cancer cell identity and function. Citation Format: Yin Zhang, Yong-xin Huang, Dan-lan Wang, Hai-yan Yan, Yin Dong. A lineage-specific lncRNA driven by Foxa1 associated super enhancer promotes tumor growth through interacting YBX1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3702.
COVID-19 Transmission Conclusions Justified by the Analysis Results?
Authors: Fu-Chang Hu
Journal: JAMA Internal Medicine (2020)

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Abstract 4616: Functional genomic analyses of 21q22.3 locus identify potential functional variants and candidate gene <i>YBEY</i> for breast cancer risk
Authors: Chris Shidal, Xiang Shu, Jie Wu, Jifeng Wang, Shuya Huang, Joshua Bauer, Xingyi Guo, Wei Zheng, Xiao-Ou Shu, Qiuyin Cai
Journal: Cancer Research (2020)

Abstract We have previously identified SNP rs3541811, located in the 21q22.3 locus, to be associated with breast cancer risk in Asians. However, the underlying causal functional variants and gene(s) responsible for this association are unknown. In this study, we performed functional genomic analyses to identify potential functional variants and target genes that may mediate this association. Functional annotation for SNPs highly correlated with rs3541881, using epigenetic data from the Encyclopedia of DNA Elements (ENCODE) and Roadmap projects, showed evidence of promoter and/or enhancer activities of five putative functional SNPs, including rs35418111, rs2078203, rs8134832, rs57385578, and rs8126917. These SNPs were assessed for interactions with nuclear proteins by EMSA assay. Our results showed that compared to the reference allele, alternate allele rs2078203 (A &amp;gt; G) significantly increased DNA-protein interactions, while an opposite trend was observed for rs35418111 (G &amp;gt; A). Cis-expression quantitative loci (eQTL) analysis, using data from the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and the Shanghai Breast Cancer Study, indicated that the risk allele rs35418111 is associated with a decreased expression of the YBEY (C21or57) gene, indicating its putative oncogenic function that may contribute to breast cancer risk. The gene YBEY is a relatively uncharacterized endoribonuclease in humans, which is thought to function in rRNA cleavage and maturation, similar to its bacterial homologues. We further investigated whether YBEY may have any biological effect in human breast cancers by knocking-down YBEY gene expression using siRNA in MCF-7, T47D, and MDA-MB-231 cell lines. Transient knockdown of YBEY gene expression in three breast cancer cell lines consistently affected cell proliferation, colony formation, and migration/invasion, regardless of hormone receptor status. Our study provides support for a significant role for human YBEY gene in breast cancer pathogenesis and the association between the rs35418111/21q22.3 locus and breast cancer risk, which may be mediated through its correlated potential functional SNPs that regulate expression of the YBEY gene. Citation Format: Chris Shidal, Xiang Shu, Jie Wu, Jifeng Wang, Shuya Huang, Joshua Bauer, Xingyi Guo, Wei Zheng, Xiao-Ou Shu, Qiuyin Cai. Functional genomic analyses of 21q22.3 locus identify potential functional variants and candidate gene YBEY for breast cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4616.