MP17-07 IDENTIFYING NOVEL THERAPEUTIC TARGETS BASED ON PERTURBATION OF BLADDER CANCER CELLULAR CIRCUITRY USING METAGENOMICS

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (MP17)1 Apr 2020MP17-07 IDENTIFYING NOVEL THERAPEUTIC TARGETS BASED ON PERTURBATION OF BLADDER CANCER CELLULAR CIRCUITRY USING METAGENOMICS Anirban P Mitra* Anirban P Mitra*Anirban P Mitra* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000842.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Several novel therapeutics have been approved for bladder cancer treatment based on empiric observations of overexpression in tumors, without much significance attributed to their overall role in altering the circuitry within cancer cells. This study employed metagenomics to interrogate previously described prognostic biomarkers to identify molecules that represent the confluence of cellular networks affected during bladder carcinogenesis and progression. The hypothesis is that central molecules may be ideal therapeutic targets regardless of differential expression as they coordinate several cellular circuits crucial to the tumor's survival. METHODS: Prior profiling studies were reviewed to identify protein-coding genes associated with bladder cancer prognosis. After excluding non-mappable genes, curated pathway analyses were used to enumerate direct and indirect interactions between mRNAs within the context of merged biological networks. Top ranking molecules, defined by the highest %ile of interactions, were evaluated for their value as therapeutic targets. RESULTS: 825 genes were used to construct two interactomes. 8,776 direct and indirect molecular interactions were noted. Identified genes were %ile-ranked based on number of interactions with neighboring genes within curated pathways. 78 molecules contributed to the top 90 %ile of all interactions. 27%, 14%, 19% and 28% of these molecules are typically located in the extracellular, plasma membrane, cytoplasmic and nuclear compartments, respectively. Top canonical pathways included intranuclear and death receptor signaling, T cell modulation, and interleukin signaling. Associated cellular functions included cell death, cell-cycle regulation, cell proliferation, and cellular movement. Merged analysis identified eight molecules (TNF, ERBB2, IL1B, APP, EGFR, FYN, VEGFA, ABL1) in the top 90 %ile with associated monoclonal antibodies or small molecule inhibitors (top tox pathway p ≤ 3.84E-10); several of these have not been tested in bladder cancer. Another nine molecules that are variously influenced by chemotherapeutics were also identified. CONCLUSIONS: This study describes a metagenomic approach using prior prognostic biomarkers that may be used to identify druggable targets in bladder cancer. This paradigm may be employed in the setting of an individual patient to flag molecules that play putative central roles in modulating the tumor's molecular circuitry, and may therefore be a consensus target and potentially minimize the probability of tumor escape. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e228-e228 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anirban P Mitra* More articles by this author Expand All Advertisement PDF downloadLoading ...