ZIA BC 011648 (ZIA) | |||
---|---|---|---|
Title | Targeting Genetic and Metabolic Alterations in Distinct Subtypes of RCC | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Srinivasan, Ramaprasad | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $549,081 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (30.0%) Metastasis (70.0%) |
Kidney Disease (100.0%) Urinary System (100.0%) Kidney Cancer (100.0%) |
||
Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Systemic Therapies - Clinical Applications |
|||
Abstract | |||
Kidney cancer is comprised of a wide array of histologically and genetically diverse tumors that arise in the kidney. Several subtypes of RCC, distinguishable by unique clinical and histological features, are now recognized. Additionally, by studying familial forms of RCC and more recently, by large scale genomic analysis, a variety of genetic alterations associated with these unique RCC subtypes have been unearthed. The identification of distinct molecular pathways in individual RCC subtypes has served as the foundation for our approach to the evaluation of individualized, mechanism based treatment strategies for these patients. Our group is pursuing a variety of approaches as highlighted below: 1) Targeting the Met pathway in papillary RCC: Papillary RCC, accounting for 10-15% of all kidney cancers, is comprised of a heterogeneous group of malignancies characterized by the presence of papillae on histopathologic evalaution. A major scientific interest within the UOB Molecular Therapeutics program is to better characterize the molecular and mechanistic basis of the various subtypes of papillary RCC. As part of a dedicated translational effort to develop mechanism based therapeutic strategies for papillary RCC, a variety of systemic approaches targeting both conventional oncogenes and altered metabolic pathways are being evaluated. Germline activating mutations in the proto-oncogene MET are the basis for the development of bilateral multifocal type 1 papillary tumors in families with a condition termed Hereditary Papillary Renal Cell Cancer (HPRC). In addition, the MET pathway appears to be activated in a subset of patients with sporadic papillary RCC. To determine the relevance of MET as a valid therapeutic target, we helped design and conduct the first trial of a MET tyrosine kinase inhibitor, foretinib (an agent with additional activity against VEGFR2), in patients with papillary RCC. Data from this proof of concept, multicenter phase 2 trial were published in the Journal of Clinical Oncology, and demonstrated the efficacy of this approach in papillary RCC, particularly in patients with germline activating mutations in MET. However, dosing of this agent was limited by toxicity related to VEFGR inhibition and it is unclear if optimal MET inhibition was achieved with this drug. We hypothesized that selective MET inhibitors might provide maximal target inhibition with acceptable toxicity. This hypothesis is being evaluated in a phase 2 trial of INC280, a selective, second generation MET inhibitor. 2) Targeting Metabolic Alterations in Papillary RCC: A second well studied biochemical alteration in papillary RCC is the preferential utilization of aerobic glycolysis and activation of an oxidative stress response mechanism, best characterized in tumors from patients with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), who carry germline inactivating mutations in the gene for the Krebs' cycle enzyme fumarate hydratase. A targeted approach to these tumors is being studied in an ongoing phase 2 study of bevacizumab and erlotinib. Interim analyses have shown a high response rate (ORR approximately 65% in those with fumarate hydratase mutations) and durable responses in many patients, including those with some forms of sporadic papillary RCC. Based on the unprecedented efficacy seen in the phase 2 trial of bevacizumab and erlotinib, efforts are afoot to further evaluate this regimen as a feasible and effective standard of care option in patients with familial as well as sporadic forms of papillary RCC. As part of this strategy, the study has been expanded in order to confirm the response rates seen initially as well as to attempt to identify molecular markers that may help identify sporadic papillary RCC patients most likely to benefit from this approach. A variety of other approaches are also being investigated in a bid to exploit the dependence of some forms of papillary RCC on aerobic glycolysis; a phase 1/2 trial of vandet |