This is an application for a NIDDK Mentored Clinical Scientist Development Award for Peter E. Clark, M.D. and is in response to NOT-DK-03-004: NIDDK Career Development Programs for Urologic Surgeons. Advanced renal cell carcinoma (RCC) is a deadly, chemotherapy resistant disease usually treated with biologic therapy such as interferon alpha (IFNa). New forms of therapy for advanced RCC are needed. Apo2 ligand/Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a member of the TNF superfamily and is an attractive potential anti-tumor agent as it induces apoptosis preferentially in malignant cells. TRAIL is well tolerated in animal tumor models and preliminary clinical trials are ongoing in various cancers, including RCC. TRAIL mediated apoptosis is dependent on its death domain (DD) containing cognate receptors, DR4 and DR5, as well as the DD adaptor molecule FADD. TRAIL mediated signaling may be modulated by two receptors that lack a functional DD, DcR1 and DcR2 and by other downstream regulators of apoptosis (FLIP, Bel family members, etc.). This project examines three complementary aspects of TRAIL receptor signaling in RCC. Our preliminary studies indicate that IFNa and TRAIL cooperate to increase RCC cell death.
In aim one we will determine the molecular mechanism by which this occurs. In other cancers the expression of TRAIL and its receptors predicts outcome but this has not been studied in RCC.
In aim two we will analyze a large well characterized cohort of RCC patients to determine the expression level of TRAIL and its cognate receptors and test if this predicts clinical outcome. Finally, functionally significant somatic mutations exist in DR4 and DR5 in a variety of cancers but this has not been studied in RCC.
In aim 3 we will identify mutations in RCC and determine their functional significance. Together, these studies provide a detailed picture of the role of TRAIL in RCC and could provide a mechanistic basis for combining TRAIL with IFNa as therapy for RCC and using TRAIL receptor levels and/or mutations as clinical prognostic markers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA113452-03
Application #
7127664
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Myrick, Dorkina C
Project Start
2005-09-29
Project End
2010-08-31
Budget Start
2007-09-07
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$127,794
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Polosukhina, Dina; Love, Harold D; Correa, Hernan et al. (2017) Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors. Mol Oncol 11:405-421
Polosukhina, Dina; Love, Harold D; Moses, Harold L et al. (2017) Pharmacologic Inhibition of ?-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor. Oncol Res 25:1653-1664
Kaffenberger, Samuel D; Lin-Tsai, Opal; Stratton, Kelly L et al. (2015) Statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma. Urol Oncol 33:21.e11-21.e17
Morgan, Todd M; Seeley, Erin H; Fadare, Oluwole et al. (2013) Imaging the clear cell renal cell carcinoma proteome. J Urol 189:1097-103
Kaffenberger, Samuel D; Morgan, Todd M; Stratton, Kelly L et al. (2012) ABO blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma. BJU Int 110:E641-6
DeGraff, David J; Clark, Peter E; Cates, Justin M et al. (2012) Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One 7:e36669
Clark, Peter E; Polosukhina, Dina; Love, Harold et al. (2011) ?-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors. Am J Pathol 179:3045-55
Morgan, Todd M; Tang, Dominic; Stratton, Kelly L et al. (2011) Preoperative nutritional status is an important predictor of survival in patients undergoing surgery for renal cell carcinoma. Eur Urol 59:923-8
Clark, Peter E (2010) Rationale for targeted therapies and potential role of pazopanib in advanced renal cell carcinoma. Biologics 4:187-97
Clark, Peter E; Polosukhina, Dina A; Gyabaah, Kenneth et al. (2010) TRAIL and interferon-alpha act synergistically to induce renal cell carcinoma apoptosis. J Urol 184:1166-74

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