# RP-1: Defining Predictors of Sensitivity to Cisplatin-Based Chemotherapy in Urothelial Cancer

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $368,437

## Abstract

Project Summary/Abstract
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is a standard of care
for the curative-intent treatment of muscle-invasive bladder cancer (MIBC). This project is based on the
scientific premise that prospective molecular profiling can identify patients with MIBC (cT2-4aN0M0) for whom
transurethral resection of the bladder tumor (TURBT) and systemic chemotherapy is curative without the need
for RC. It builds upon prior retrospective data demonstrating that 1) deleterious alterations in DNA damage
response (DDR) genes, most frequently in the nucleotide excision repair gene ERCC2, are predictive of
response to cisplatin-based combination chemotherapy in MIBC and 2) small cohorts of patients who achieve
clinical complete responses to NAC and refuse or are medically unfit for RC survive long-term with their
bladders intact. The hypothesis that select patients with MIBC can be successfully managed with TURBT and
chemotherapy alone, without the need for RC, will be tested in Aim 1 in the context of a prospective,
multicenter clinical trial performed by the Alliance for Clinical Trials in Oncology (A031701). In this study, pre-
treatment diagnostic TURBT samples will undergo next-generation sequencing analysis of 468 cancer-
associated genes. All patients will receive dose-dense gemcitabine and cisplatin for 6 cycles followed by
clinical re-staging and will be managed with either bladder preservation or RC based upon 1) post-
chemotherapy response as assessed by repeat cystoscopy, TURBT, and imaging, and 2) somatic mutation
status of DDR-related genes in the patient's pre-treatment tumor. Patients with deleterious somatic alterations
in at least 1 of 9 DDR-associated genes who achieve a clinical complete response or down-staging to
noninvasive disease (<cT1) following NAC will be candidates for bladder preservation. Patients with DDR gene
mutations who have ≥cT1 disease after chemotherapy will undergo RC, as will all DDR gene wild-type
patients, regardless of response. Recognizing that ~60% of NAC responders lack somatic DDR gene
alterations, whole exome sequencing will be performed in Aim 2, using the tumor material collected pre-
treatment from all patients enrolled on A031701, to identify additional biomarkers of chemo-sensitivity,
including mutation signatures of DDR deficiency. In Aim 3, we will assess whether analysis of cell-free DNA
from blood and urine is a sensitive, noninvasive method to identify patients with minimal residual disease and
to explore tumor heterogeneity and its relationship to drug resistance and disease recurrence. The proposed
studies rely extensively on support from the Biospecimen Repository and the Biostatistics & Bioinformatics
Core to achieve the project's translational objectives. If successful, the studies proposed could significantly
expand the use of organ-sparing therapy for the curative-intent treatment of patients with MIBC. The
prospective molecular char...

## Key facts

- **NIH application ID:** 10226969
- **Project number:** 5P50CA221745-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** David B. Solit
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,437
- **Award type:** 5
- **Project period:** 2018-08-24 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226969

## Citation

> US National Institutes of Health, RePORTER application 10226969, RP-1: Defining Predictors of Sensitivity to Cisplatin-Based Chemotherapy in Urothelial Cancer (5P50CA221745-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226969. Licensed CC0.

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