SAN FRANCISCO, CA USA (UroToday.com) - The slogan for the GU Cancers Symposium this year was “Integrating biology into patient care,” and Dr. Sabina Signoretti gave a talk that was in line with this mission statement.
She began by highlighting the role of VHL pathway in the genesis of clear cell renal cell carcinoma (ccRCC). New sequencing technologies have uncovered mutations in chromatin modifying genes and metabolic pathways, but these findings have not really translated into significantly improved patient outcomes. The hypoxia inducible factors (HIFs), which are targets of the VHL pathway, have both tumor suppressing and oncogenic members. HIF1-alpha is lost in ~40% of ccrCCs when chromosome 14q is lost, suggesting it is a tumor suppressor. This theory was validated in animal experiments. These findings suggest that both VHL and HIF1-alpha must be lost during the genesis of ccRCC, establishing HIF2-alpha as the primary oncogenic driver of the VHL pathway. Based on this hypothesis, Dr. Signoretti evaluated VHL pathway as a predictive tool in response to pazopanib. However, her lab was not able to show that its expression, nor expression of HIF1-alpha, nor VHL expression correlated with patient outcomes for those who are treated with pazopanib.
She also presented data regarding mTOR pathway mutations. Mutations of genes in this pathway are observed in about 15% of ccRCCs, but individual genes in this pathway are only mutated in 1-5% of ccRCCs. This prompted the hypothesis that genes with mutations in this pathway might be sensitive to mTOR inhibitors. This was confirmed when analyzing a small cohort of patients with “outlier responses” to everolimus or temsirolimus. To conclude, although VHL pathway alterations seem central to the genesis of ccRCC, pathway components do not seem to correlate with therapy response, but the opposite might be true for mTOR pathway component alterations and drug sensitivity.
Highlights of a presentation by Sabina Signoretti, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
The Dana-Farber Cancer Institute, Boston, MA USA