Molecular Therapeutics of Kidney Cancer-MET Gene and BHD Gene Understanding the genes that cause kidney cancer provides the opportunity to develop approaches for molecular therapeutics for this disease. We have identified 3 genes that cause cancer of the kidney: the VHL gene (clear cell renal cell carcinoma);the c-Met gene (papillary type 1 renal carcinoma);and the BHD gene (chromophobe renal carcinoma). Targeting the MET Gene: Type 1 Papillary Kidney Cancer We have found activating mutations of the MET gene in the germline of patients with Hereditary Papillary Renal Cell Carcinoma (HPRC) as well as in a subset of tumors from patients with sporadic, type 1 papillary kidney cnacer Studies are underway to target the c-Met type 1 papillary kidney cancer gene pathway in papillary kidney cancer. The Met gene codes for a cell surface receptor for a systemically circulating growth factor, hepatocyte growth factor (HGF). The germline mutations identified in the HPRC kindreds and somatic mutations of the c-Met oncogene in sporadic type 1 papillary renal carcinoma are located in the tyrosine kinase domain of the MET gene and are predicted to activate this receptor. In-vitro and in-vivo studies are underway to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of type 1 papillary renal carcinoma. Targeting the BHD Gene: Chromophobe Kidney Cancer The BHD gene is the gene for the inherited form of chromophobe kidney cancer associated with Birt-Hogg-Dub syndrome. When we found the BHD gene it was a novel gene with no known function. Studies are currently underway to determine what type cancer gene the BHD gene, how it functions normally and how damage to this gene leads to chromophobe renal carcinoma. We have identified mutations of the BHD gene in 94% of the BHD families tested. In order to determine what type of gene the BHD gene is we searched for mutation of the second copy of the gene in kidney tumor specimens from BHD patients. We found mutation (or loss of heterozygosity) of the second copy (the wild type copy) of the BHD gene in 70% of the tumor samples evaluated. These findings provided the evidence that the BHD gene is a loss of function, tumor suppressor gene. When we found the BHD gene it was a novel gene with unknown function. In order to determine what the function of the BHD gene is we performed studies to determine which proteins bind to the BHD protein (called folliculin). We found that folliculin binds to a novel protein, called FNIP1 (folliculin interacting protein) that FNIP1 binds to AMPK, which is the cells main energy sensing protein. AMPK phosphorylates both FNIP1 and AMPK and FNIP phosphorylate folliculin. AMPK inhibits the function of MTOR through the TS pathway. We found that MTOR phosphorylates folliculin and that this phosphorylation is inhibited in-vitro by treatment with rapamycin. We have subsequently found that folliculin binds to a second protein, FNIP2, which also binds AMPK and which is also phosphorylated by AMPK and that AMPK/FNIP2 phosphorylate folliculin. Folliculin and FNIP1 and FNIP2 co-localize in the cytoplasm and the binding of folliculin to FNIP1 and FNIP2 is in the carboxy terminus of the protein. The finding that the germline BHD mutations are predominantly mutations that are predicted to truncate the protein (frameshift or nonsense mutations) suggests that folliculin binding to FNIP1/FNIP2 is critical to folliculins tumor suppressor function. In order to develop a BHD animal model to further understand the effect of mutation of the BHD gene and to provide a model for evaluation of targeted therapeutics we developed a kidney specific BHD knockout mouse. In this model BHD -/- mice developed large cystic kidneys with areas of hyperplastic tissues. These animals develop renal insufficience and survive for only 30 days. In order to evaluate the effect of a targeted therapeutic approach for the BHD gene pathway the BHD -/- animals were treated with rapamycin. The rapamycin treated animals had a significant diminution in the kidney phenotype and their survival was doubled. We have developed a unique in-vitro model of a human kidney cancer cell line from a BHD patient and are evaluating multiple agents with target the BHD pathway in our in-vivo and in-vitro models. These studies provide the basis for the development of a targeted therapeutic approach for BHD-associated kidney cancer and for a subset of patients with sporadic, non-inherited chromophobe kidney cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011043-06
Application #
8763320
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$1,749,632
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Ricketts, Christopher J; Crooks, Daniel R; Sourbier, Carole et al. (2016) SnapShot: Renal Cell Carcinoma. Cancer Cell 29:610-610.e1
Srivastava, Apurva K; Hollingshead, Melinda G; Weiner, Jennifer et al. (2016) Pharmacodynamic Response of the MET/HGF Receptor to Small-Molecule Tyrosine Kinase Inhibitors Examined with Validated, Fit-for-Clinic Immunoassays. Clin Cancer Res 22:3683-94
Hankins, Ryan A; Walton-Diaz, Annerleim; Truong, Hong et al. (2016) Renal functional outcomes after robotic multiplex partial nephrectomy: the National Cancer Institute experience with robotic partial nephrectomy for 3 or more tumors in a single kidney. Int Urol Nephrol 48:1817-1821
Scelo, G; Hofmann, J N; Banks, R E et al. (2016) International cancer seminars: a focus on kidney cancer. Ann Oncol 27:1382-5
Baba, Masaya; Toyama, Hirofumi; Sun, Lei et al. (2016) Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure. Stem Cells 34:1068-82
Hasumi, Hisashi; Baba, Masaya; Hasumi, Yukiko et al. (2015) Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proc Natl Acad Sci U S A 112:E1624-31
Srinivasan, Ramaprasad; Ricketts, Christopher J; Sourbier, Carole et al. (2015) New strategies in renal cell carcinoma: targeting the genetic and metabolic basis of disease. Clin Cancer Res 21:10-7
Schmidt, Laura S; Linehan, W Marston (2015) Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12:558-69
Prieto, Darue A; Johann Jr, Donald J; Wei, Bih-Rong et al. (2014) Mass spectrometry in cancer biomarker research: a case for immunodepletion of abundant blood-derived proteins from clinical tissue specimens. Biomark Med 8:269-86
Alimchandani, Meghna; Lara, Karlena; Tsokos, Maria et al. (2014) Lymphangitic retroperitoneal carcinomatosis occurring from metastatic sarcomatoid chromophobe renal cell carcinoma. Urol Case Rep 2:39-62

Showing the most recent 10 out of 111 publications