Gain-of-function p53 mutations are important biomarkers for Hsp90 inhibitors

p53 is a well-known tumor suppressor that prevents cancer formation. More than 50% of human tumors contain a mutation or deletion of p53. Li-Fraumeni syndrome, a rare inherited disorder that greatly increases the risk of developing cancers, is caused by heterozygous mutations of p53.

Mutant p53 (mutp53) proteins not only lose their tumor suppressor functions, but also gain oncogenic functions that promote cancer cell survival. Li-Fraumeni patients with gain-of-function p53 mutations have shorter tumor-free survival than those with loss of p53 expression (p53-null).

Cancer researchers at Stony Brook University and Synta Pharmaceuticals (NASDAQ: SNTA) showed that tumors with gain-of-function p53 mutations depend on sustained mutp53 expression[1]. The Hsp90/HDAC6 chaperone machinery is a major determinant of mutp53 stabilization.

The researchers treated Q/- (R248Q mutation), H/H (R172H mutation) and p53-null mice with weekly doses of Hsp90 inhibitor ganetespib. The drug benefited only mutp53 mice but not p53-null mice, extending the survival of Q/- mice and H/H mice by 59% and 48%, respectively.

ganetespib

Synta is testing ganetespib in patients with second-line NSCLC in a Phase III trial (GALAXY-2).

In the previous Phase II/III trial (GALAXY-1), median overall survival for ganetespib/docetaxel was 9.8 months compared to 7.4 months for docetaxel. The result was not statistically significant.

Subgroup analysis showed that ganetespib/docetaxel significantly improved overall survival (10.7 vs. 6.4 months) in patients with diagnosis of advanced disease greater than 6 months. The GALAXY-2 trial excludes rapid progressors.

Investors don’t buy the subgroup analysis, as usual. Synta shares have plummeted more than 70% since 2013. I have no confidence in the GALAXY-2 trial as well. Anyhow, the study of p53 mutations will help Synta select right patients.

[1] Nature. 2015, doi: 10.1038/nature14430.

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