# Defining the roles of PPARgamma and TGFbeta in regulating NECTIN4 and resistance to NECTIN4-targeting therapies

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $268,867

## Abstract

PROJECT SUMMARY
The goal of this K08 application is to provide Dr. Jonathan Chou, an Instructor of Medicine at UCSF, with the
skills he will need to become an independently-funded laboratory investigator. Dr. Chou proposes to elucidate
the regulatory mechanisms of NECTIN4, the target of a newly approved antibody-drug conjugate (ADC) in
metastatic urothelial cancer called enfortumab vedotin (EV) and identify mechanisms of resistance using PDX
and metastatic biopsy samples. The proposal builds on Dr. Chou’s recent work, which showed that NECTIN4
expression is enriched in luminal subtypes of bladder cancer, and that increasing and decreasing NECTIN4 can
enhance EV sensitivity or lead to resistance, respectively. Dr. Chou hypothesizes that the transcription factor
PPARG, which regulates luminal bladder cancer cell identity and integrates fatty acid signaling, is a direct
regulator of NECTIN4 and that transiently augmenting NECTIN4 expression in urothelial cancer cells will
enhance the efficacy of NECTIN4-targeting therapies. In Aims 1 and 2, Dr. Chou will elucidate the mechanism
underlying this regulatory pathway and determine whether sensitivity to NECTIN4-targeted therapies can be
enhanced by directly modulating the PPARg pathway using pharmacologic approaches, biological modifiers and
dietary alterations. In Aim 3, Dr. Chou will determine whether loss of PPARg or alternatively, activation of the
EMT-associated TGFb pathway downregulates NECTIN4, thus leading to resistance. He will leverage EV-
resistant cell lines that he has generated, patient-derived xenograft (PDX) models (established from minority
patients treated at UCSF), as well as metastatic biopsy samples from UCSF patients treated on EV, to
accomplish this Aim. Dr. Chou’s training and research plan includes a combination of structured coursework and
workshops, one-on-one tutorials, and hands-on research experience that will all take place at UCSF, a world-
renowned NCCN Cancer Center with a history of excellence in basic and translational cancer research. Dr.
Chou’s training plan will complement his existing expertise to build a strong foundation in the following areas: 1)
bladder cancer biology; 2) preclinical modeling of ADCs and adoptive T cell therapies; 3) cancer metabolism and
drug resistance; and 4) genomics and next-generation sequencing methods and analysis. The project will be
conducted under the mentorship of Dr. Felix Feng, Professor of Radiation Oncology and Associate Director for
Translational Sciences, and co-mentored by Dr. Alan Ashworth, Professor of Medicine and President of the
UCSF Cancer Center. He has assembled a distinguished advisory panel with complementary expertise to guide
his research and career path. At the completion of this award, Dr. Chou will have the relevant didactic and
research experience to become a leader in bladder cancer models, therapeutic targeting strategies and genomic
approaches to investigate drug resistance, including to ADCs. If successfu...

## Key facts

- **NIH application ID:** 10691485
- **Project number:** 5K08CA273514-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jonathan Chou
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $268,867
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691485

## Citation

> US National Institutes of Health, RePORTER application 10691485, Defining the roles of PPARgamma and TGFbeta in regulating NECTIN4 and resistance to NECTIN4-targeting therapies (5K08CA273514-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10691485. Licensed CC0.

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