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
Nadal, Rosa; Apolo, Andrea B (2018) Overview of Current and Future Adjuvant Therapy for Muscle-Invasive Urothelial Carcinoma. Curr Treat Options Oncol 19:36
Siefker-Radtke, Arlene O; Apolo, Andrea B; Bivalacqua, Trinity J et al. (2018) Immunotherapy with Checkpoint Blockade in the Treatment of Urothelial Carcinoma. J Urol 199:1129-1142
Patel, Manish R; Ellerton, John; Infante, Jeffrey R et al. (2018) Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:51-64
Harshman, Lauren C; Tripathi, Abhishek; Kaag, Matthew et al. (2018) Contemporary Patterns of Multidisciplinary Care in Patients With Muscle-invasive Bladder Cancer. Clin Genitourin Cancer 16:213-218
Powles, Thomas; Necchi, Andrea; Rosen, Galit et al. (2018) Anti-Programmed Cell Death 1/Ligand 1 (PD-1/PD-L1) Antibodies for the Treatment of Urothelial Carcinoma: State of the Art and Future Development. Clin Genitourin Cancer 16:117-129
Bagheri, Mohammad H; Ahlman, Mark A; Lindenberg, Liza et al. (2017) Advances in medical imaging for the diagnosis and management of common genitourinary cancers. Urol Oncol 35:473-491
Machado, Laura B; Apolo, Andrea B; Steinberg, Seth M et al. (2017) Radiology Reports With Hyperlinks Improve Target Lesion Selection and Measurement Concordance in Cancer Trials. AJR Am J Roentgenol 208:W31-W37
Apolo, Andrea B; Infante, Jeffrey R; Balmanoukian, Ani et al. (2017) Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol 35:2117-2124
Harmon, Stephanie A; Perk, Timothy; Lin, Christie et al. (2017) Quantitative Assessment of Early [18F]Sodium Fluoride Positron Emission Tomography/Computed Tomography Response to Treatment in Men With Metastatic Prostate Cancer to Bone. J Clin Oncol 35:2829-2837
Apolo, Andrea B; Karzai, Fatima H; Trepel, Jane B et al. (2017) A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma. Clin Genitourin Cancer 15:77-85

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