Recent advances in the understanding of the genetic and metabolic basis of renal cell carcinoma (RCC) may lead to personalized therapies with improved survival rates, according to the authors of a review published in Clinical Cancer Research.1
Despite considerable progress, much remains to be done against this aggressive disease. Each year, more than 270,000 people worldwide are diagnosed with RCC and nearly 120,000 die of it.
New Approaches to Clear-Cell RCC
Clear-cell RCC accounts for approximately three-fourths of RCC cases. The VHL tumor suppressor gene is implicated in more than 90% of clear-cell RCC tumors, but targeting the VHL/HIF pathway is only partially successful against this form of the disease, according to the review authors.
Response rates of up to 45% and improved progression-free survival have been achieved, but eventually almost all patients develop progressive disease.
Whether we need different ways to target the VHL/HIF pathway or need to target other pathways to improve response rates is unknown. Concurrent inhibition of multiple pathways is under investigation, but so far the results have been disappointing, with few long-term responses or complete remissions.
Several research labs are investigating agents that target HIF2ɑ, which may be a critical downstream target of VHL, and have produced intriguing preclinical results.
Chromatin-remodeling gene mutations also may be important targets in the treatment of clear-cell RCC. Genetic studies have pointed to a fundamental role for aberrant chromatin biology in RCC and have identified numerous mutations associated with altered chromatin regulation.
Multiregion exome sequencing of clear-cell RCC tumors has demonstrated a high degree of heterogeneity within tumors, complicating the search for effective treatments. VHL gene mutations were found in each case, however, suggesting that these are “truncal” mutations and should be the primary focus of research.
Advanced-stage clear-cell RCC shows evidence of a metabolic shift, suggesting that glutaminase, AMPK, FAS, and LDHA are potential therapeutic targets.