tbuckley/cabot-search huggingface dataset:
Abstract 235: Identifying potential drug targets using patient-derived, tissue specific, gene regulatory networks
Authors: Andre Neil Forbes, Duo Xu, Ekta Khurana
Journal: Cancer Research (2021)

Abstract Recent developments in sequencing have allowed consortiums like ENCODE and ROADMAP to probe the epigenome of normal and cancer cell lines. Applying these approaches in a broad fashion to patient data has been difficult but a pioneering TCGA study using ATAC-Seq, an assay for probing open chromatin and thus regulatory regions, provides an opportunity to analyze cancer patient epigenomes for key regulators and potential drug targets. Utilizing this TCGA dataset, we identify the regulatory targets of open chromatin regions as assayed by ATAC-Seq and RNA-Seq across 371 patients on a patient-specific basis. We subsequently utilize transcription factor (TF) footprinting to identify regions bound by 850 TF &amp;TF-families in each patient. The final output of this approach identifies which TF regulates individual genes for every patient. Using a combination of network metrics and TF abundance, we can identify known and rare subtypes of multiple cancers with similar underlying networks. We next identify a set of TFs with greater importance and predicted activity within each cluster of samples relative to others. To expand the set of potentially druggable genes, we use data from the Achilles/DepMap project to identify a set of genes whose essentiality is most highly correlated with the set of critical TFs for each cluster, i.e. “coessential genes”. We next combine our list with two datasets, the list of known druggable genes and the Drug Interaction Database to identify compounds that target this gene set. We prioritize genes highly correlated with our key TFs' essentiality, are not pan-cancer essential genes or targeted by drugs with high inferred toxicity. We identify a set of neuroendocrine-like cancers in lung and stomach adenocarcinoma, rare disease subtypes in their representative cancers. Further investigation finds these samples expressing high levels of known neuroendocrine markers synaptophysin and PCSK1. Within well-studied cancers like breast and colon adenocarcinoma we identify separate ER+ and ER- sample clusters as well as MSI-H samples as separate and featuring different key TFs than MSI-L and MSS clusters. Our drug candidate pipeline identified known targeted drugs in breast cancer such as Tamoxifen and Fulvestrant, non-specific chemotherapies like doxorubicin in addition to the novel candidates Nelfinavir and Indinavir as potential therapeutic agents. In summary we identify key TFs in multiple cancers and novel drugs for targeting those TFs or downstream effectors. Citation Format: Andre Neil Forbes, Duo Xu, Ekta Khurana. Identifying potential drug targets using patient-derived, tissue specific, gene regulatory networks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 235.
Improving the inclusion rate in clinical trials of bladder cancer patients by mapping the quality process of the multidisciplinary team
Authors: N. Vidal, J. Gómez Rivas, M.I. Galante, I. De La Parra, T. Jerez, J.L. Gonzalez Larriba, C. Toledano, L. Fernandez-Montarroso, E. Redondo, J. Moreno-Sierra, J. Puente
Journal: European Urology (2021)
A multicentre based critical analysis of laser settings during intrarenal laser lithotripsy
Authors: M.G. Sönmez, S. Guven, A Tuncel, I. Karabulut, O. Kilic, I. Seckiner, T. Tefik, G. Atis, G. Ergin, V. Tuğcu, B. Erkurt, A. Muslumanoglu, K. Sarıca
Journal: European Urology (2021)
Abstract 2324: A novel oncogene mediated metabolic gene signature predicts breast cancer outcome
Authors: Merve Aslan, En-Chi Hsu, Fernando J. Garcia Marques, Abel Bermudez, Michelle Shen, Meghan A. Rice, Shiqin Liu, Robert West, Sharon J. Pitteri, Balázs Győrffy, Tanya Stoyanova
Journal: Cancer Research (2021)

Abstract Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in the US, with triple negative breast cancer (TNBC) as the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed nearly all epithelial cancers including triple negative breast cancer. In this study, we demonstrate that loss of Trop2 derives downregulation of metabolic genes. Trop2 oncogene-driven metabolic gene signature is highly elevated in breast cancer patients and predicts poor outcome. Methods: Trop2 expression levels in two independent patient cohorts were analyzed with immunohistochemistry. Trop2 was knockdown in TNBC cell line HCC1806 with shRNA and knock-out in HCC1806 with CRISPR Cas9 system. Trop2 downregulation or gene deletion effect was tested in vitro with colony formation and 3D Matrigel invasion assays. The effect of Trop2 downregulation in tumorigenesis was evaluated in vivo by subcutaneous implantation of control and Trop2 knockdown xenografts. Proteomic changes were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Trop2 led to downregulation of TALDO1 associated metabolic cluster genes which expression levels were further investigated in four independent breast cancer cohort. Finally, the correlation of Trop2 oncogene-driven metabolic gene signature with breast cancer outcome was analyzed in 13 independent breast cancer patient datasets. Results: We demonstrate Trop2 is overexpressed in TNBC, and downregulation of Trop2 disrupts TNBC cell and tumor growth. Through whole proteomic profiling, we discovered a novel metabolic cluster that was downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-driven metabolic gene signature is significantly upregulated in TNBC patients across multiple clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stage of the disease. Conclusion: Our study identifies a new five gene metabolic oncogene-driven signature as a prognostic predictor of breast cancer. Citation Format: Merve Aslan, En-Chi Hsu, Fernando J. Garcia Marques, Abel Bermudez, Michelle Shen, Meghan A. Rice, Shiqin Liu, Robert West, Sharon J. Pitteri, Balázs Győrffy, Tanya Stoyanova. A novel oncogene mediated metabolic gene signature predicts breast cancer outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2324.
Abstract 2825: Mechanosurveillance by immunity targets mechanical compliance of metastatic cells
Authors: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calo, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er
Journal: Cancer Research (2021)

Abstract Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells' expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B's established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells' stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases. Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calo, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance by immunity targets mechanical compliance of metastatic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2825.
Transperineal Targeted Microwave Ablation (TMA) of anterior midline prostate cancer using minigrid and Organ Based Tracking (OBT)
Authors: P.K-F. Chiu, J.Y. Teoh, S.Y. Lau, H.F. Wong, C.H. Yee, K.L. Lo, C.C-M. Cho, T.Y. Yuen, H.Y. Hung, C.K. Chan, S.M. Hou, C.F. Ng
Journal: European Urology (2021)
Reply
Authors: Safoora Fatima, O. Schieir, E. C. Keystone, M. F. Valois, S. J. Bartlett, L. Bessette, G. Boire, G. Hazlewood, C. Hitchon, D. Tin, C. Thorne, V. P. Bykerk, J. E. Pope
Journal: Arthritis & Rheumatology (2021)

We appreciate the interest in our manuscript concerning the Health Assessment Questionnaire disability index (HAQ) in an early rheumatoid arthritis incident cohort (the CATCH cohort) which predicted all-cause mortality (1). We will clarify queries raised in letters to the editor (2-4).
癌細胞幹細胞性の阻害に関連する低酸素刺激腫瘍治療【JST・京大機械翻訳】
Authors: Wang Fang, Luo Rengan, Xin Hao, Zhang Yaming, J Cordova Wong Bernardino, Wang Weiping, Lei Jianping
Journal: Biomaterials (2020)
Physical Activities in Patients with β-Thalassemia As Measured By Fitbit in Association with Patient-Reported Outcomes
Authors: Antonis Kattamis, Pranee Sutcharitchan, Ali Taher, Maria Domenica Cappellini, Dalia Mahmoud, Joseph Pariseau, Abderrahmane Laadem, Anzalee Khan, X. Henry Hu, Vip Viprakasit
Journal: Blood (2017)
Abstract 44: The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer
Authors: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor
Journal: Cancer Research (2021)

Abstract ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of &amp;gt;90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 44.
Abstract 975: Antitumor effect of cyclin- dependent kinase inhibitor flavopiridol in c-Myc overexpressing esophageal cancer
Authors: Md Sazzad Hassan, Niranjan Awasthi, Jun Li, Margaret A. Schwarz, Urs von Holzen
Journal: Cancer Research (2021)

Abstract Tumors with elevated c-Myc expression often exhibit highly aggressive phenotype and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting a synthetic-lethal approach dependent on elevated c-Myc signaling is effective in treating esophageal cancer with a CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth without association with improved overall survival in esophageal cancer patients. c-Myc expression was enhanced by Wnt signaling activator (6-bromoindirubin-3′ -oxime (BIO) or pcDNA3-cMyc and c-Myc expression was depleted by c-Myc siRNAs. Interestingly, esophageal cancer cells with elevated c-Myc expression were preferentially more sensitive to induction of apoptosis by CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combinations with chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth with significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to CDK inhibitor flavopiridol and flavopiridol alone or in combination with cytotoxic or targeted agents can be a potential therapy for c-Myc overexpressing esophageal cancer. Citation Format: Md Sazzad Hassan, Niranjan Awasthi, Jun Li, Margaret A. Schwarz, Urs von Holzen. Antitumor effect of cyclin- dependent kinase inhibitor flavopiridol in c-Myc overexpressing esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 975.
Abstract 3064: Investigation of ionizing radiation response in new resistance models of glioblastoma
Authors: Nareg Pinarbasi, Tugba Bagci-Onder, Ilknur Sur Erdem, Ugur Selek
Journal: Cancer Research (2021)

Abstract Glioblastoma is one of the most aggressive central nervous system tumors, which constitutes 50% of all primary brain tumors. Glioblastomas have a very poor prognosis, approximately 12-15 months even with standard therapy. Current treatment protocols include surgery, chemotherapy, and radiotherapy. High rates of recurrence after treatment, genetic heterogeneity, and developing resistance to chemotherapy and radiotherapy are challenges to overcome in glioblastoma treatment. Therefore, developing models of chemo- or radio-resistance is of priority to understand the molecular mechanisms that operate during the transition of cells to therapy-refractory state, and to develop new therapeutic approaches. In this study, we generated ionizing radiation (IR)-exposed glioblastoma cell populations to investigate molecular alterations associated with acquired radiotherapy resistance. To generate a clinically relevant radioresistance model, we have exposed glioblastoma cells to a total dose of 60 Gy IR over a 6-week period and cultured age-matched parental cells. We successfully generated sustainable radioresistant cells, as demonstrated by cell viability and colony formation assays. RNA sequencing, performed on these matched cell lines revealed major alterations in the expression of genes of the cell cycle, DNA damage recognition, and repair machinery in the radioresistant cells. Specifically, elements of the DNA double strand break (DSB) recognition and repair, such as ATM, ATR, and CHK1 were markedly upregulated in the radioresistant cell populations. In line with these findings, DNA repair capacity of the radioresistant cell populations was increased, as revealed by the faster clearance of H2AX and 53BP1 in the radioresistant populations. Complementing this approach, pharmacological inhibition of major DNA damage response elements, such as ATM, ATR, as well as CHK1 markedly sensitized the radioresistant cells. Our results prepare a groundwork for studying the molecular mechanisms of radiotherapy resistance and developing novel combination therapy strategies for glioblastomas. Citation Format: Nareg Pinarbasi, Tugba Bagci-Onder, Ilknur Sur Erdem, Ugur Selek. Investigation of ionizing radiation response in new resistance models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3064.
Abstract 2091: DNA methylation enhances apoptosis resistance of renal cancer cells
Authors: Kosuke Miyakuni, Jun Nishida, Shogo Ehata, Kohei Miyazono
Journal: Cancer Research (2021)

Abstract Epigenetic modifications are important not only for carcinogenesis but also for metastasis of clear cell renal cell carcinoma (ccRCC). We previously reported that inflammation-related signaling is constitutively activated in advanced ccRCC through the formation of super enhancer. In addition to histone modification, methylation of the primary structure of DNA is implicated in the progression of ccRCC. Recent studies revealed that DNA hypermethylation was frequently observed in ccRCC and correlated with poor prognosis. However, unlike in other cancers, methylated genes responsible for cancer progression is still unclear in ccRCC. In this study, we tried to identify a target(s) for DNA methyltransferases (DNMTs) in ccRCC cells based on the genome-wide analysis. Its function for the regulation of cellular survival was examined. Our preclinical model of ccRCC using the serial orthotopic inoculation model exhibited the up-regulation of DNMT3B in advanced ccRCC. Pre-treatment of advanced ccRCC with 5-aza-dC attenuated a formation of a primary tumor through the induction apoptosis. DNA methylated sites were analyzed using methylation array in reference to RNA-sequencing data. As a result, ubiquinol cytochrome c reductase hinge protein (UQCRH), one of the components of mitochondrial complex III, was extracted as a methylation target in advanced ccRCC. Immunohistochemical analysis revealed that the expression of UQCRH in human ccRCC tissue was lower than normal adjacent tissue. Silencing of UQCRH attenuated the cytochrome c release in response to apoptotic stimuli and resulted in enhancement of primary tumor formation in vivo. Our results imply that DNA methylation induces the decreased expression of potential tumor suppressor gene UQCRH, which is essential for the completion of apoptotic process of ccRCC cells. These findings may contribute to the understanding of molecular mechanisms involved in the drug resistance of ccRCC cells and provide an important insight for the improvement of the efficacy of existing medicines. Citation Format: Kosuke Miyakuni, Jun Nishida, Shogo Ehata, Kohei Miyazono. DNA methylation enhances apoptosis resistance of renal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2091.
2dFDR: a new approach to confounder adjustment substantially increases detection power in omics association studies
Authors: Sangyoon Yi, Xianyang Zhang, Lu Yang, Jinyan Huang, Yuanhang Liu, Chen Wang, Daniel J. Schaid, Jun Chen
Journal: Genome biology (2021)

Abstract One challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.
Diagnostic and prognostic factors in patients with prostate cancer
Authors: K. Beyer, L. Moris, M. Lardas, A. Haire, F. Barletta, S. Scuderi, M. Molnar, R. Herrera, A. Rauf, R. Campi, I.. Greco, K. Shiranov, S. Dabestani, T. Van Den Broeck, M. Gacci, G. Gandaglia, M.I. Omar, S. Maclennan, M.J. Roobol, J. Zong, S.J. Maclennan, L. Collette, A. Briganti, A. Bjartell, M. Van Hemelrijck
Journal: European Urology (2021)