# Project 1: Combinatorial Molecular Tumor Drivers in Basal and Supra-                 basal Urothelial Cells

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $336,319

## Abstract

Project 1 Summary
One of the key challenges confronting the accurate diagnosis and effective treatment of cancer is its
heterogeneous nature. This is particularly true with bladder cancer (BC) which is now known to comprise
principal histological types (transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma and small
cell carcinoma), major phenotypic variants within the most prevalent transitional cell carcinoma (low-grade
papillary BC and high-grade invasive BC) and molecular subtypes within the muscle-invasive BC (such as
luminal-subtype and basal-subtype). Importantly, different BC entities appear to be quite divergent in biological
behavior, clinical outcome and response to therapies. However, the exact mechanism(s) underlying BC
heterogeneity remain poorly understood, thus presenting a major hindrance for rapid and meaningful clinical
translation of the basic science discoveries. The present proposal is therefore designed to address this
important and pressing problem by specifically targeting a set of genetic and molecular events highly prevalent
in human BC into different cell populations of murine urothelia. Specific Aim 1 will interrogate key mutational
events that activate the RTK-PI3K-RAS pathway, in conjunction with the loss of tumor suppressors in the 9p21
locus, in the context of the formation of low-grade papillary BC. Aim 2 will dissect the combinatorial driver
effects of p53 deficiency along with altered DNA repair genes/histone modifiers, in the context of the formation
of high-grade invasive BC and potentially its subtypes. The experimental approaches will combine the
generation and in-depth characterization of transgenic, knockin, knockout and compound mice. Together, the
proposed studies should significantly enhance our understanding of the genetic, molecular and cellular bases
of BC heterogeneity. This should in turn lead to the development of new biomarker panels that can more
reliably stratify BC variants, more accurately predict their probability of progression and likelihood to respond to
chemo-, radio- and immuno-therapeutics. The true genetic, molecular and cellular identification of BC variants
should also help uncover new targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10455729
- **Project number:** 5P01CA165980-09
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** XUE-RU WU
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,319
- **Award type:** 5
- **Project period:** 2013-09-12 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455729

## Citation

> US National Institutes of Health, RePORTER application 10455729, Project 1: Combinatorial Molecular Tumor Drivers in Basal and Supra-                 basal Urothelial Cells (5P01CA165980-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455729. Licensed CC0.

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