Defining the roles of PPARgamma and TGFbeta in regulating NECTIN4 and resistance to NECTIN4-targeting therapies - 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 successful, this project will also provide a translational opportunity from the laboratory to the clinic, to utilize dietary modifications and thiazolidinedione drug combinations to augment responses and potentially reverse resistance to NECTIN4-targeting therapies.
