A study has unveiled a potential new weapon in the fight against metastatic castration-resistant prostate cancer (mCRPC). Researchers have found that pimitespib, a drug already approved in Japan for treating gastrointestinal tumors, could help overcome resistance to therapies like enzalutamide, darolutamide, and abiraterone, offering hope for patients with limited options.

In mCRPC, cancer cells evade these androgen receptor pathway inhibitors (ARPIs) through mechanisms like overactive androgen receptors (AR), mutated AR forms, a variant called AR-V7, alternative glucocorticoid receptor (GR) signaling, and activation of the AKT pathway. These processes allow tumors to keep growing despite treatment. Pimitespib targets heat shock protein 90 (HSP90), a molecule that stabilizes these resistance-driving proteins, disrupting their function and potentially restoring the effectiveness of ARPIs.

The study tested pimitespib in four prostate cancer cell lines and two animal models of castration-resistant prostate cancer. In the lab, pimitespib boosted the power of the three ARPIs, rapidly blocking AR and GR from entering the cell nucleus within an hour of treatment. This prevented the activation of genes that fuel cancer growth. The drug also reduced levels of AR, GR, AR-V7, and AKT proteins, effectively dismantling the molecular defenses behind ARPI resistance. Gene analysis confirmed that pimitespib shut down the activity of these resistance-related proteins.

In animal models, pimitespib enhanced the tumor-shrinking effects of ARPIs, with the combination of pimitespib and enzalutamide proving particularly effective and safe, showing no significant added toxicity. These findings suggest that pimitespib could be a game-changer for mCRPC patients who no longer respond to standard therapies.
While the results are promising, experts caution that clinical trials are needed to confirm pimitespib’s effectiveness and safety in humans.

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