ZIA BC 011028 (ZIA) | |||
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Title | Clinical Studies of the Molecular Genetic Basis of Kidney Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Linehan, W. Marston | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $440,152 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (5.0%) |
Central Nervous System - Not Including Brain (5.0%) Eye (5.0%) Kidney Disease (75.0%) Nervous System (5.0%) Pancreas (5.0%) Urinary System (75.0%) Uterine (5.0%) Kidney Cancer (75.0%) |
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Research Type | |||
Localized Therapies - Discovery and Development Systemic Therapies - Discovery and Development |
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Abstract | |||
Our work has shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer, each with a different histology, a different clinical course, responding differently to therapy and each caused by a different gene. Our approach has been to identify the genes that cause kidney cancer in order to provide the foundation targeted therapeutic approaches to this disease. In order to identify the genes that cause kidney cancer we have studied the inherited forms of cancer of the kidney. Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are a number of different types of inherited kidney cancer including: 1) von Hippel Lindau (VHL), the inherited form of clear cell renal carcinoma; 2) Hereditary Papillary Renal Carcinoma (HPRC), hereditary Type 1 kidney cancer, 3) Birt Hogg Dub (BHD), the inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC), type 2 papillary renal carcinoma. In order to develop new methods for treatment of patients with sporadic as well as familial kidney cancer we established an NIH kidney cancer working group involving clinicians and investigators from 29 different laboratories and branch from 9 different NIH Institutes. Individuals affected with von Hippel Lindau (VHL) are at risk for the development of bilateral, multifocal clear cell kidney cancer as well as tumors in the brain, spine, eyes, pancreas, adrenal gland and inner ear. By studying VHL families we were able to perform genetic linkage analysis to localize and subsequently identify the VHL gene on chromosome 3. We have identified the VHL gene mutation in the germline of 246/246 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating novel minimally invasive forms of therapy for kidney and adrenal tumors in VHL. We have described the surgical management of VHL kidney cancers as well as VHL pheochromocytoma, pancreas tumors, ear tumors and brain and spine tumors. We currently have two clinical trials in progress targeting the VHL gene pathway in patients affected with VHL. We have shown that the VHL gene is also the gene for the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). In a series of studies we have identified mutation/methylation of the VHL gene in up to 92% of tumors from patients with sporadic (non-inherited) clear cell kidney cancer. Study of the VHL gene pathway has provided the foundation for the development of targeted therapeutics for patients with both clear cell kidney cancer as well as von Hippel-Lindau. We currently are conducting a clinical trial of an agent which targets the VHL pathway in patients with advanced clear cell kidney cancer. In 1994 we described a novel form of inherited kidney cancer, Hereditary Papillary Renal Carcinoma (HPRC). HPRC is an inherited cancer syndrome in which affected individuals are at risk for the formation of multifocal, bilateral type 1 papillary kidney cancer. In order to identify the gene for HPRC we studied families with this rare, inherited cancer syndrome to determine which individuals had the kidney cancers and which did not. Linkage analysis performed in the families to localized the gene to the long arm of chromosome 7. The proto-oncogene, MET, was subsequently identified as the HPRC gene. We have identified activating mutations in the tyrosine kinase domain of the MET gene in the germline of the HPRC families as well as in a subset of tumors from patients with sporadic, non-inherited type 1 papillary kidney cancer. These findings provided the foundation for the development of a targeted therapeutic approach to the treatment of patients affected with HPRC as well as for patients with sporadic, non-hereditary papillary kidney cancer. We are currently conducting a clinical trial with an agent which targets the MET gene pathway in patients with Hereditary Papillary Renal Carcinoma and sporadic papillary k |