ROLE OF B-ARRESTINS IN BLADDER CANCER PROGRESSION AND RESPONSE TO CHEMOTHERAPY

Bladder cancer is the most expensive cancer to treat. Frequent recurrence and treatment refractoriness are themost common causes of morbidity and high cost of treatment of this disease. Males are three times more likelyto develop bladder cancer. Therefore, the United States Veterans are at higher risk of developing bladdercancer. The high-grade, muscle invasive bladder cancers are difficult to treat and neoadjuvant and adjuvantchemotherapies have only modest benefits for overall survival. The investigators identified a pair of molecularmarkers that potentially determine response to chemotherapy, especially towards the Gemcitabine + Cisplatinchemotherapy combination. The markers β-Arrestin 1 (BARR1) and β-Arrestin 2 (BARR2) are members of theintracellular signaling complex triggered by chemokine receptors. The research group investigated muscleinvasive bladder cancer tissues and found that BARR1 and BARR2 expressions are associated with treatmentfailure and metastasis. Further, in vitro studies using established bladder cancer cell lines showed an inversecorrelation between BARR2 levels and the cancer stem cell phenotype, metastatic potential, and resistance toGemcitabine induced cytotoxicity. Conversely, BARR1 expression correlated with metastasis and cancer stemcell properties. The principal hypothesis of this project is BARR1 and BARR2 are regulators of BC cell growth,differentiation into basal or luminal cell phenotype, and BC cell motility. BARR1 and BARR2 regulate malignantprogressions, such as muscle invasion, metastasis, and resistance to chemotherapy drugs. Three specificaims are proposed: 1. To investigate the mechanism by which BARR1 and BARR2 regulate BC growth, cancerstem cell phenotype, and invasive/metastatic potential; 2. To investigate whether modulation of the levels ofBARR1 and BARR2 alters the response to Gem treatment in preclinical BC models. Also, test the potential oftetrahydrouridine, an inhibitor of intracellular Gemcitabine metabolism, to sensitize chemotherapy-resistantPatient-derived bladder tumor xenografts (PDX) towards Gemcitabine; 3. To investigate the potential ofBARR1 and BARR2 expression as a predictor of chemotherapy response and clinical outcome in MIBC. Theinvestigators consider the high impact of this project on improving the prediction of treatment-response in high-grade bladder cancers as well as therapy response using a combination of a non-toxic drug and an establishedchemotherapy drug. The proposed studies have the potential to improve bladder cancer treatment andoutcome for U.S. Veterans.