Two-drug combo reverses prostate cancer's escape route — SkimNews
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- University of Michigan researchers found that combining BET bromodomain inhibitors with DNMT inhibitors reversed significant gene expression changes and sharply slowed tumor growth in prostate cancer cell lines and mouse models of transdifferentiated disease.
- BET bromodomain inhibitors alone slowed but did not kill cancer cells, prompting the team to add DNMT inhibitors—which reactivate silenced glandular genes—to attack the second half of the cellular identity switch.
- Joshi Alumkal's team tied resistance to loss of the TP53 and RB1 genes, which triggers transdifferentiation: cancer cells shed their glandular identity and activate stem-cell-like programs, explained the professor of internal medicine at Michigan Medicine.
- DNMT inhibitors have already received FDA approval for other conditions, including blood cancer, which could shorten the path to clinical trials of the combination in prostate cancer patients.
- Lead researcher Will Storck said the drug combination produced a significant reduction in tumor growth at doses far lower than the recommended dose and was well tolerated by the mice.
- Researchers now aim to identify biomarkers that predict which patients' tumors are most likely to undergo transdifferentiation, so the combination could be deployed before tumors finish reshaping their identity.
- The team believes the dual-target strategy could extend beyond prostate cancer to lung and pancreatic cancers that undergo similar cellular identity changes.
Why it matters: Prostate cancer is the second leading cause of cancer death in American men, and nearly all metastatic patients on androgen receptor inhibitors eventually develop resistance. A combination of two drug classes—one already FDA-approved—reversed the cellular identity shift behind that resistance in preclinical models, offering a concrete candidate strategy for the roughly one in eight men who will be diagnosed with prostate cancer.
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