Project 2: The Role of Nuclear Receptors Signaling in Bladder Cancer

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Abstract

Urothelial carcinoma (bladder cancer; BC) is currently the 6th most common form of cancer in the United States with about 81,000 new cases and 17,000 deaths per year. It occurs 3 times more frequently in men than in women, but women tend to have more aggressive disease. Most cases of BC (70%) present as non-muscle invasive bladder cancer (NMIBC), which are relatively benign but can progress to muscle invasive bladder cancer (MIBC), which is associated with a 50% five-year survival rate, and metastatic progression almost always leads to death. Given the risk associated with NMIBC progression, identification of potential mechanisms and druggable pathways that can slow or prevent growth at early stages is an important goal. While there are mouse models that can be induced to form Basal/Squamous tumors, at present there are few models of NMIBC that produce luminal/papillary tumors in in situ. Mutations that activate PPARG are common in human LP NMIBC. We've developed a new BBN-induced mouse model propelled by a constitutively active form of Pparg (VP16; Pparg). Expression of VP16;Pparg in basal progenitors using the Krt5CreERT2 driver, induces formation of LP tumors within 3-5 months, closely resembling human tumors histologically and at the molecular level. Our studies that RA-signaling and Kdm6a, promoters of luminal differentiation, and suppressors of BSQ differentiation are induced in parallel or down-stream from Pparg. In Aims 1 and 2 of this application we will characterize the LP model and assess the requirement for retinoids in tumor formation. KDM6A is commonly mutated in human BC. We will examine the function of these mutations in the context of LP NMIBC using our Pparg driven model in Aim 2 and we will determine Kdm6a regulates RA-signaling. We find that activation of Pparg signaling has potent anti-tumor activity in mouse model of BBN-induced MIBC; and shifts tumor subtype from BASQ to luminal. Preliminary analysis reveals that RA treatment also exhibits anti-tumor activity in BBN-induced MIBC. In Aim 3, we will compare the effects of Pparg activation with that of retinoids to evaluate their anti-tumor activity and effects on subtype. The goal of these proposed studies is to use preclinical models to identify and characterize cellular and molecular mechanisms driving tumor formation, with an ultimate goal of identification of drugs that may be used in a clinical setting for preventing or inhibiting growth of BASQ and LP tumors.