# Targeting ARID1A mutated Urothelial Carcinoma

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10703720
- **Project number:** 1I01BX005765-01A2
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** Sumati Gupta
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10703720

## Citation

> US National Institutes of Health, RePORTER application 10703720, Targeting ARID1A mutated Urothelial Carcinoma (1I01BX005765-01A2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10703720. Licensed CC0.

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