Two-Drug Combo Slows Aggressive Prostate Cancer in Mice

Scientists at the University of Michigan have found a promising new way to fight aggressive prostate cancer that has stopped responding to standard treatments.

The research team discovered that combining two types of drugs, BET bromodomain inhibitors and DNMT inhibitors, worked better together than either drug alone at slowing cancer growth in lab tests and mice. Both drug types are already FDA-approved for other conditions, which could speed up the path to human trials.

The breakthrough targets a major challenge in prostate cancer treatment. While androgen receptor inhibitors work well at first, nearly all patients eventually develop resistance. Some tumors adapt by completely changing their identity through a process called transdifferentiation, making them harder to treat.

Lead researcher Dr. Joshi Alumkal explained that losing two genes, TP53 and RB1, triggers this dangerous transformation. His team identified two separate pathways involved: the loss of normal glandular genes and the activation of programs that turn cells into stem cells.

Previous research showed that BET bromodomain inhibitors could slow cancer growth by blocking alternate identity programs, but the drugs couldn't kill the cancer cells completely. The team then added DNMT inhibitors, which help turn glandular genes back on and reverse some of the cancer's identity changes.

The combination worked remarkably well. In mice with implanted tumors, the dual treatment significantly reduced tumor growth even at doses far lower than standard recommendations. The mice tolerated the treatment well without serious side effects.

"When we used both drugs, we reversed a significant portion of gene expression changes that occur in the tumors, which is encouraging," said Will Storck, a research specialist on the team.

The Bright Side

The findings published in JCI Insight could extend beyond prostate cancer. The researchers believe their approach might work for other transdifferentiated cancers, including those in the lungs and pancreas. That means this discovery could eventually help thousands of patients facing different types of aggressive cancer.

The team is now working to identify which specific genes account for the anti-tumor effects they observed. They also want to find biomarkers that can predict which patients would benefit most from the treatment.

An even more exciting possibility is preventing transdifferentiation before it starts. Alumkal noted that distinguishing between patients whose tumors will undergo this transition versus those that won't could help doctors use the treatment early and effectively.

The researchers are planning new clinical trials to test whether this drug combination will work in patients with transdifferentiated prostate cancer. With one in eight men diagnosed with prostate cancer during their lifetime, and the disease being the second-leading cause of cancer-related death in men, effective treatments for resistant forms could save countless lives.