Scientists find a new weakness in treatment-resistant prostate cancer

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

Most prostate tumors initially resemble the glands of the prostate and express genes associated with glandular cells. Their growth also commonly depends on androgens, male hormones such as testosterone.

Because of this dependence, androgen receptor inhibitors are a mainstay of treatment for metastatic prostate cancer. These drugs can work well at first, but nearly all patients eventually develop resistance.

How Prostate Cancer Changes To Escape Treatment

Some resistant prostate tumors survive by activating alternative biological pathways that reshape the identity of their cells. As this happens, the cancer cells lose some of their glandular characteristics and begin adopting other cellular identities.

Scientists call this process transdifferentiation.

In a new study published in JCI Insight, researchers at the University of Michigan identified two pathways that may be targeted at the same time to treat prostate tumors that have undergone this transformation.

The researchers believe the strategy could eventually have implications beyond prostate cancer. They hope similar approaches might work against other cancers that undergo transdifferentiation, including cancers of the lung and pancreas.

Earlier research had linked the loss of two genes, TP53 and RB1, with transdifferentiation in prostate cancer. Exactly why losing those genes causes such a dramatic change in tumor cell identity, however, remained unclear.

To investigate, the researchers examined several prostate cancer cell lines and studied which cellular pathways changed when TP53 and RB1 were missing.

"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, M.D., Professor of Internal Medicine-Hematology/Oncology and member of Rogel Cancer Center.

Two Drug Classes Target Different Sides of the Cancer Shift

The research team had previously shown that drugs known as BET bromodomain inhibitors can interfere with pathways that allow prostate cancer cells to activate alternative identity programs.

However, those drugs alone did not permanently stop the cancer from progressing.

In the new experiments, the researchers again found that BET bromodomain inhibitors slowed the growth of prostate cancer cell lines. The drugs, however, did not kill the cancer cells.

That led the team to investigate a second group of drugs called DNA methyltransferase, or DNMT, inhibitors.

DNMT inhibitors can reactivate genes that have been switched off. In this case, researchers were particularly interested in restoring glandular genes that are often lost as prostate cancer cells change identity.

These inhibitors have already received FDA approval for other conditions, including blood cancer.

Drug Combination Slows Prostate Tumor Growth

Researchers then combined BET bromodomain inhibitors with DNMT inhibitors.

Using the two types of drugs together suppressed the growth of prostate cancer cell lines more effectively than either drug used by itself.

The researchers saw a similar effect in prostate 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 findings suggest that targeting both sides of the cancer cell transformation could be more effective than blocking only one of them. One drug interferes with programs that promote an alternative cellular identity, while the other helps restore glandular gene activity that has been lost.

Searching for the Patients Most Likely To Benefit

The researchers now want to determine which genes are primarily responsible for the antitumor effects seen in the experiments.

They also want to identify biomarkers that could reveal which patients are most likely to benefit from the drug combination.

Another major question is whether treatment could stop transdifferentiation before it happens, rather than trying to treat tumors after they have already changed identity.

"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 team hopes to develop clinical trials to determine whether combining BET bromodomain and DNMT inhibitors can benefit patients with transdifferentiated prostate cancer.

Researchers are also interested in testing whether the same two-drug approach could work against other cancers that undergo similar changes in cellular identity.