New Drug Combination May Help Treat Advanced Prostate Cancer

About one in eight men are diagnosed with prostate cancer during their lifetime.

Although many survive, it can develop into metastatic disease.

In the United States, prostate cancer is the second-leading cause of cancer-related death in men.

Most prostate cancers have an appearance that resembles glands and they express glandular genes.

They also depend on androgens, male hormones like testosterone, for their growth.

For this reason, androgen receptor inhibitors are the primary treatment in metastatic prostate cancer.

Although these drugs are initially effective, nearly all patients eventually become resistant to treatment.

Some of these resistant tumors adapt by activating different pathways that ultimately change the blueprint of the cells, making them less glandular and allowing them to take on different identities.

This process is called transdifferentiation.

In a new study published in JCI Insight¹, University of Michigan researchers identified two pathways that can simultaneously be targeted to treat transdifferentiated prostate tumors.

They hope that their findings can also be applied to other transdifferentiated cancers, including those in the lungs and pancreas.

Previous studies have shown that losing the genes TP53 and RB1 is associated with transdifferentiation in prostate cancer.

However, the underlying reasons were not well understood.

The team first looked at different prostate cancer cell lines to see which cell pathways were affected when TP53 and RB1 were absent.

Previously, the team had shown that a class of drugs called BET bromodomain inhibitors can block the pathways that allow prostate cancer cells to turn on alternate identity programs.

However, these drugs failed to permanently block disease progression.

In the present study, the researchers confirmed that although the BET bromodomain inhibitors could slow down growth of the cancer cell lines, they weren’t able to kill them.

They then focused on using DNA methyltransferase, or DNMT, inhibitors that can turn genes back on, including the glandular genes that change the identity of prostate cancers and are often lost.

These inhibitors have been approved by the FDA for other disorders like blood cancer.

The researchers found that using both BET bromodomain and DNMT inhibitors suppressed the growth of prostate cancer cell lines better compared to drug alone.

The same results were true in tumors implanted in mice.

“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, Ph.D., Research Lab Specialist in the Alumkal lab.

“It is also promising that we saw a significant reduction in tumor growth even at doses far lower than the recommended dose and this drug combination was well tolerated by the mice.”

The researchers want to better understand which specific genes account for the anti-tumor effects they observed in the study and whether there are specific biomarkers that can identify which patients would benefit from the drug combination.

They are also interested in understanding whether they can block transdifferentiation before the process begins.

“Preventing the emergence of transdifferentiation would be key to patient survival,” Alumkal said.

“Distinguishing between patients whose tumors will never undergo this transition versus patients whose tumors may will help us use this treatment effectively and early.”

The researchers hope to develop new clinical trials to see whether this drug combination will work in patients with transdifferentiated prostate cancer.

They are also hopeful that using both types of inhibitors simultaneously will work in other types of transdifferentiated cancer.

Reference:

1) https://insight.jci.org/articles/view/207543

(Newswise/HG)