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Principal Investigator: Sumati Gupta
Organization: VA SALT LAKE CITY HEALTHCARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Bladder cancer is the most common urinary tract cancer in men. The cumulative effects of smoking and
deployment-related carcinogens in the aging Veteran population play a major role in the pathogenesis of
bladder cancer. The recurring and progressive nature of bladder cancer poses a significant health burden for
Veterans and the Veterans Health Administration. A tendency to relapse and acquire resistance to treatment
is a recurrent theme in all stages of the disease. Epigenetic alterations are widely prevalent in bladder cancer
and are a challenge to target due to the wide-ranging effects of chromatin modifications. We focus on the most
common chromatin alteration in bladder cancer, which is ARID1A gene mutation, and broaden the scope of our
study to address treatment resistance in all bladder cancer. Treatment resistance is linked to the mutation or
deletion of tumor suppressor gene, ARID1A, in early stages. ARID1A gene mutations are present in about a
fourth of bladder cancer, through all stages of the disease, and play a role in bladder cancer stem cell
maintenance, renewal and therapy resistance. ARID1A protein is a subunit of the SWI/SNF chromatin
remodeling complex. It has a concerted role in controlling cell proliferation, differentiation and protecting the
genome from damage. Targeting loss of this multi-faceted tumor suppressor is a daunting undertaking and
hence, there is currently no specific therapy for ARID1A mutated cancer. We characterize ARID1A mutated
bladder cancer in a multi-omics context, combining gene alterations, protein enrichment and gene expression
changes, and correlating clinical course to identify pathways of treatment resistance. The pathways of
treatment resistance that we have identified in ARID1A mutated bladder cancer are active and prevalent in all
bladder cancer. We have identified specific treatments that are likely to be highly effective in the setting of
treatment resistance. We plan to: 1. Establish the mechanisms of treatment resistance and aggressive disease
biology in all bladder cancer 2. Establish combinations of highly effective treatments to overcome aggressive
treatment-resistant bladder cancer. We use datasets of clinically annotated molecularly sequenced tumors and
archived tissue to validate and consolidate our targets. We have characterized cell lines, patient-derived
tumors, and highly effective precise therapeutic agents to test our hypotheses. We use sophisticated assays to
understand the mechanisms that drive cancer growth and spread. Currently, there is no targeted therapy for
treatment-resistant bladder cancer. Our multi-disciplinary collaboration and innovative multi-omics approach
will lead to a paradigm of effective targeting and provide an enduring treatment outcome for bladder cancer in
Veterans.
Terms: <ARID1A><ARID1A gene><AT- rich interactive domain-containing protein 1A><AT-rich interactive domain 1A gene><Address><Aging><Anti-Oncogenes><Antioncogenes><Archives><Assay><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Biology><Bladder Cancer><Cancer Causing Agents><Cancer Induction><Cancer Model><Cancer Relapse><Cancer Suppressor Genes><Cancer cell line><CancerModel><Cancers><Carcinogen exposure><Carcinogens><Categories><Cell Body><Cell Communication and Signaling><Cell Growth and Maintenance><Cell Growth in Number><Cell Line><Cell Maintenance><Cell Multiplication><Cell Proliferation><Cell Signaling><CellLine><Cells><Cellular Proliferation><Chromatin><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Clinical><Clinical Course of Disease><Clinical Trials><Combined Modality Therapy><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data Bases><Data Set><Databases><Disease><Disease Resistance><Disorder><Drug Synergism><Drugs><ERK 2><ERK2><ERT1><Emerogenes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evolution><Extracellular Signal-Regulated Kinase 2><Gene Alteration><Gene Combinations><Gene Expression><Gene Mutation><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetic mutation><Genome><Growth><Health><Health Resources Administration><Histones><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Interdisciplinary Research><Interdisciplinary Study><Intracellular Communication and Signaling><Link><MAP Kinase 1><MAP Kinase 2><MAP kinase><MAPK1><MAPK1 Mitogen-Activated Protein Kinase><MAPK1 gene><MAPK2><MAPK2 Mitogen-Activated Protein Kinase><MEK inhibition><MEKs><Malignant Bladder Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Bladder><Malignant Urinary Tract Neoplasm><Malignant neoplasm of urinary bladder><Mediating><Medication><Mitogen Activated Protein Kinase 1><Mitogen-Activated Protein Kinase 2><Mitogen-Activated Protein Kinases><Modeling><Molecular><Molecular Sequence Data><Molecular Target><Multidisciplinary Collaboration><Multidisciplinary Research><Multimodal Therapy><Multimodal Treatment><Multiomic Data><Mutate><Mutation><Nature><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncogenic><Oncogens><Oncology><Oncology Cancer><Outcome><P41MAPK><P42MAPK><PRKM1><PRKM2><Pathogenesis><Pathway interactions><Patients><Pharmaceutical Preparations><Play><Process><Prognosis><Proteins><Proteome><RNA Expression><Recessive Oncogenes><Recurrence><Recurrent><Recurrent disease><Relapse><Relapsed Disease><Renal/Urologic Organ System><Research><Research Priority><Resistance><Role><Sequence Alteration><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smoking><Source><Strains Cell Lines><System><TCGA><Testing><The Cancer Genome Atlas><Therapeutic Agents><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transitional Carcinoma><Transitional Cell Carcinoma><Translating><Treatment Failure><Treatment outcome><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumor Suppressor Proteins><Tumor Tissue><United States Health Resources Administration><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Urinary Tract Cancer><Urinary system><Urologic Cancer><Urologic/Renal Body System><Urological Cancer><Urothelial Carcinoma><Urothelium><Variant><Variation><Veterans><Veterans Health Administration><Veterans Health Affairs><aggressive therapy><aggressive treatment><biological signal transduction><cancer cell><cancer progenitor><cancer progenitor cells><cancer progression><cancer stem cell><carcinogenesis><chemotherapy><chromatin modification><chromatin modifier><chromatin remodeling><combination therapy><combined modality 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efficacy><precision cancer care><precision cancer medicine><precision oncology><preclinical><preclinical assessment><preclinical efficacy><programs><resistance to disease><resistance to therapy><resistant><resistant disease><resistant to disease><resistant to therapy><response to therapy><response to treatment><self-renew><self-renewal><social role><survivorship><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapy failure><therapy resistant><therapy response><tissue archive><transcription factor><treatment resistance><treatment response><treatment responsiveness><tumor><tumor initiation><tumor progression><tumor suppressor><veteran population>