The focus of my work has been to develop targeted therapies for the treatment of urothelial cancer and to further our understanding of the pathways driving this disease, specifically the angiogenesis pathway. I am Principle Investigator of two first line studies for metastatic bladder cancer using lenalidomide in combination with chemotherapies. Lenalidomide possess anti-angiogenic and immunomodulating properties, making it an ideal drug to explore in urothelial carcinoma. I explored in vitro combinations of lenalidomide with cisplatin, gemcitabine and carboplatin and found the combination of lenalidomide with chemotherapy has a clear and dose-dependent enhancement of anti-proliferative activity in T24 urothelial cancer cell lines. In addition to studying the VEGF pathway, evidence derived from our group, in collaboration with Dr. Donald Botarro, supports the cooperative roles for MET and VEGFR2 in the proliferation and survival of the tumor endothelium. Inhibition of MET can amplify the effects of VEGFR blockade. In a cohort of patients with metastatic and muscle-invasive urothelial cancer from my clinic, we analyzed blood serum and urine for soluble MET levels. MET levels in the urine were significantly higher in patients with visceral metastasis and serum MET levels were higher in patients with metastatic disease. We studied cabozantinb, a dual MET and VEGFR inhibitor (among other MET inhibitors) in urothelial cancer cells and found that MET receptor expression increased at higher disease grade. Urothelial cancer cells responded to HGF stimulation with increased activation of established intracellular signaling mediators, invasion, and anchorage-independent growth. Cabozantinib reverses these HGF-driven activities. These finding provided a rational to study cabozantinib in urothelial cancer. I initiated A Phase II Study of Cabozantinib (XL184) in Patients with Metastatic Urothelial Carcinoma. This study is ongoing and rapidly accruing patients. Based on the impressive responses we have seen to date with cabozantinib in patients with advanced, refractory urothelial cancer, I am working on designing a national phase III randomized clinical trial. This will be the first phase III study using a targeted agent in the second-line therapy of urothelial cancer in the United States.
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