Two-Drug Combination Shows Promise Against Treatment-Resistant Prostate Cancer

Prostate cancer is diagnosed in about one in eight men during their lifetime and is the second-leading cause of cancer-related death among men in the United States. Most prostate tumors depend on androgens — male hormones such as testosterone — for growth, which is why androgen receptor inhibitors are the main treatment for cancer that has spread beyond the prostate. These drugs often work at first, but nearly all patients eventually develop resistance.

Some resistant tumors escape treatment through transdifferentiation, a process in which cancer cells activate alternative pathways, lose their glandular characteristics and adopt a different cellular identity. Earlier research had linked the loss of two genes, TP53 and RB1, to this transition, though what drove the connection remained unclear.

University of Michigan researchers examined several prostate cancer cell lines to see which pathways changed when TP53 and RB1 were missing, and identified two pathways that could be targeted at once, according to a study published in JCI Insight. "We saw that there are two sides to this transition: loss of glandular genes and activation of cell programs that cause the identity to switch into stem cells," said Joshi Alumkal, professor of internal medicine at the University of Michigan's Rogel Cancer Center.

The team's earlier work had shown that drugs called BET bromodomain inhibitors could interfere with the pathway that lets prostate cancer cells switch identity, though the drugs did not permanently halt the disease. In the new study, the researchers combined BET bromodomain inhibitors with DNA methyltransferase (DNMT) inhibitors — drugs already approved by the FDA for other conditions, including blood cancers, that can reactivate genes switched off during the transition. The combination suppressed cancer cell growth more effectively than either drug alone, in cell lines and in tumors implanted in mice, even at doses far below the recommended dose, and mice tolerated it well.

"When we used both drugs, we reversed a significant portion of the gene expression changes that occur in the tumors, which is encouraging," said Will Storck, a research lab specialist in the Alumkal lab. The researchers now want to identify which genes drive the anti-tumor effect, determine whether biomarkers could identify patients most likely to benefit, and develop clinical trials to test the combination in patients with transdifferentiated prostate cancer.