Research ArticleCancer

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1

See allHide authors and affiliations

Science Translational Medicine  16 Dec 2020:
Vol. 12, Issue 574, eabb5647
DOI: 10.1126/scitranslmed.abb5647

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Putting the heat on cancer

Heat shock factor 1 is a transcription factor that helps protect healthy cells from cellular stress but can also protect tumor cells and interfere with anticancer treatment. In particular, the amount of heat shock factor 1 in the nucleus is a poor prognostic factor for patients, including those with neuroendocrine prostate cancer, an aggressive late-stage form of the disease. To target this protein, Dong et al. designed a selective small-molecule inhibitor, which directly binds nuclear heat shock factor 1 and promotes its degradation. The inhibitor was effective in multiple models of prostate cancer, including a neuroendocrine model indicating its potential for clinical testing.

Abstract

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The HSF1 gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.

View Full Text

Stay Connected to Science Translational Medicine