During my three years at the NCI I have written, designed and opened six clinical trials for bladder and prostate cancer. In less than one year I opened and completed """"""""A Phase II Study of TRC105 in Adults with Metastatic Urothelial Carcinoma"""""""". 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011351-04
Application #
8763471
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2013
Total Cost
$381,261
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Abida, Wassim; Milowsky, Matthew I; Ostrovnaya, Irina et al. (2016) Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma. Bladder Cancer 2:111-117
Tully, Christopher M; Apolo, Andrea B; Zabor, Emily C et al. (2016) The high incidence of vascular thromboembolic events in patients with metastatic or unresectable urothelial cancer treated with platinum chemotherapy agents. Cancer 122:712-21
Lin, Christie; Bradshaw, Tyler J; Perk, Timothy G et al. (2016) Repeatability of Quantitative 18F-NaF PET: A Multicenter Study. J Nucl Med :
Lerner, Seth P; Bajorin, Dean F; Dinney, Colin P et al. (2016) Summary and Recommendations from the National Cancer Institute's Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer. Bladder Cancer 2:165-202
Pham, M N; Apolo, A B; De Santis, M et al. (2016) Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer. World J Urol :
Apolo, Andrea B; Karzai, Fatima H; Trepel, Jane B et al. (2016) A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma. Clin Genitourin Cancer :
Apolo, Andrea B; Lindenberg, Liza; Shih, Joanna H et al. (2016) Prospective Study Evaluating Na18F PET/CT in Predicting Clinical Outcomes and Survival in Advanced Prostate Cancer. J Nucl Med 57:886-92
Malayeri, Ashkan A; Pattanayak, Puskar; Apolo, Andrea B (2015) Imaging muscle-invasive and metastatic urothelial carcinoma. Curr Opin Urol 25:441-8
Apolo, Andrea B; Vogelzang, Nicholas J; Theodorescu, Dan (2015) New and promising strategies in the management of bladder cancer. Am Soc Clin Oncol Educ Book :105-12
Fakhrejahani, Farhad; Tomita, Yusuke; Maj-Hes, Agnes et al. (2015) Immunotherapies for bladder cancer: a new hope. Curr Opin Urol 25:586-96

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