Scientists at Duke University School of Medicine in Durham, North Carolina, have developed a small-molecule inhibitor of the cellular stress-protective transcription factor, heat shock factor 1 (HSF1), which showed developmental promise against treatment-resistant prostate cancer and other cancers.
The well-characterized small molecule Direct Targeted HSF1 InhiBitor (DTHIB) may also be a useful research tool for investigating the regulation and role of HSF1 in basic stress biology and in cancer, the study authors reported in the December 16, 2020, edition of Science Translational Medicine (STM).
"This study describes the first direct inhibitor of human HSF1, which has been validated for efficacy in animal cancer models," said study leader Dennis Thiele, who was a professor in the Department of Pharmacology and Cancer Biology at Duke University when the study was performed.
Thiele collaborated with Jiaoti Huang, chair professor of the Department of Pathology at Duke and a leader in prostate cancer translational research and drug development, to test HSF1 inhibitors in prostate cancer cells and animal models.
Thiele is currently chief scientific officer at Sisu Pharma, a Chapel Hill, NC-based biotechnology start-up launched to develop the HSF1 inhibitor technology developed at Duke.
Various cancers use the HSF1 protein to drive their proliferation, invasion and metastasis, with nuclear HSF1 abundance being prognostic for cancer severity, treatment resistance and reduced disease-free survival.
"Besides our current work, previous studies have demonstrated that high levels of HSF1, particularly HSF1 localized to the cancer cell nucleus, are predictive of aggressive, treatment-resistant prostate cancer and shortened patient survival," said Thiele.
In prostate cancer, the HSF1 gene has been shown to be amplified, and nuclear HSF1 abundance markedly increased, particularly in untreatable neuroendocrine prostate cancer (NEPC).
Development and progression of prostate cancer requires androgen receptor (AR) signaling, which activates expression of the genes underlying prostate cancer biology.
AR antagonists and androgen deprivation by castration are well-established prostate cancer therapies, but virtually all patients eventually become therapy-resistant and progress to castration-resistant prostate cancer (CRPC) or NEPC.
"Moreover, in some patients the disease will recur as highly lethal NEPC, which does not express the AR and is resistant to AR-targeted therapies," Thiele told BioWorld Science.
"Therefore, direct inhibition of the HSF1 pathway might allow us to treat AR-dependent and AR-independent treatment-resistant prostate cancer patients who have exhausted all other therapeutic options."
Despite genetic validation of HSF1 as a therapeutic cancer target, with HSF1 genetic knockout or knockdown studies having shown efficacy in multiple animal cancer models, as yet no selective small-molecule HSF1 inhibitors have been developed or validated for clinical use.
Although HSF1 pathway inhibitors have been identified and evaluated in cellular and mouse xenograft cancer models, they either act indirectly in the HSF1 pathway or have an unknown mechanism of action.
In their new STM study, the authors used multiple biochemical experiments to show that the HSF1 inhibitor, DTHIB, binds directly to the HSF1 DNA binding genomic domain and selectively stimulate degradation of nuclear HSF1.
"In normal cells, most HSF1 is found in the cytoplasm, but in prostate cancer cells and tissues, it mostly accumulates in the cell nucleus, where it regulates the expression of genes driving prostate growth and metastasis," explained Thiele.
However, when Thiele and his team treated prostate cancer cells with DTHIB and separated them into their cytoplasmic and nuclear compartments, "cytoplasmic HSF1 levels remained unperturbed, but active nuclear HSF1 levels were rapidly degraded."
Importantly, the researchers then demonstrated that DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation in mice.
"Many of the mouse prostate cancer tumor studies have been conducted in mice with a compromised immune system to prevent rejection of implanted human tumors," noted Thiele.
"In these mice bearing human treatment-resistant prostate cancer tumors, DTHIB treatment completely halted tumor growth and resulted in an approximately 40% tumor shrinkage."
However, "in mice with a functioning immune system, tumors regressed to almost undetectable levels, suggesting that the immune system, combined with HSF1 inhibition, contributes significantly to preventing prostate cancer progression," he said.
"Finally, DTHIB-treated mice slowed the progression of prostate cancer expressing AR-v7, a form of the AR resistant to treatment with Xtandi (enzalutamide), with a tumor sample analysis having shown inhibition of the HSF1 cancer gene signature."
Moreover, DTHIB was shown to act independently of the AR and to attenuate tumor progression potently in four treatment-resistant prostate cancer animal models, including highly aggressive NEPC, in which it caused profound tumor regression.
"NEPC typically lacks AR expression and is thus not responsive to androgen deprivation therapy or AR-antagonists," Thiele told BioWorld Science.
"DTHIB administration in two mouse NEPC models resulted in significant inhibition of tumor growth," he said. "Because HSF1 is a well-validated target known to support multiple pathways for cancer growth, survival and metastasis, this suggests HSF1 inhibitors are a promising therapeutic approach for NEPC."
Regarding safety, he said, "no mice treated with DTHIB, at or exceeding the concentrations effective against prostate cancer, showed signs of toxicity, although systematic dosing studies must be conducted to evaluate the impact of administering DTHIB, or other HSF1 inhibitors."
However, "while the first-generation human HSF1 inhibitors discovered at Duke are very promising, considerable additional preclinical development is needed to optimize them for use in humans and testing in clinical trials," said Thiele.
"Because this scale of drug development activities is beyond the scope of Duke University, Sisu Pharma, has licensed the university's HSF1 inhibitor technology for further development for the treatment of PCa and other cancers." (Dong, B. et al. Sci Transl Med 2020, 12: eabb5647).