Peptides target 'undruggable' prostate cancer mutation

DNA
Peptides developed by Michigan researchers could lead to a targeted therapy for half of all prostate cancer patients.

University of Michigan researchers have identified a large molecule that selectively attacks prostate tumors that have a genetic anomaly without harming healthy cells. This mutation affects half of all prostate cancer patients.

The fusion of the genes TMPRSS2 and ERG is a key step in the development of prostate cancer, but it has been difficult to target with small-molecule drugs. Gene rearrangements are deemed poor drug targets because of their location within the cell's nucleus and absence of enzyme activity.

The Michigan team tested large-molecule peptides in animal models, finding that it disrupted ERG function and curbed the growth of prostate tumors that expressed the gene fusion. The peptides did not affect cells without ERG fusion. The research is published in Cancer Cell.

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"This is an example of how we can deliver precision therapy for prostate cancer: Only patients who have the ERG gene fusion would be matched with this agent. But it's useful because the ERG fusion is so prevalent," said senior author Arul Chinnaiyan, M.D., director of the Michigan Center for Translational Pathology and a professor of pathology at Michigan.

After skin cancer, prostate cancer is the most common cancer and the third-leading cause of cancer death in American men, according to the American Cancer Society.The five-year survival rate for local- and regional-stage prostate cancer is nearly 100%, but it drops dramatically to 28% for prostate cancer that has spread to distant lymph nodes, bones or other organs.

But some men appear to have treatable, localized cancer, yet end up developing aggressive metastasis. University of Toronto scientists pinpointed a set of genetic mutations that could help oncologists predict a patient’s risk of their cancer spreading after treatment.

Meanwhile, Tokai, which has been working on the small molecule galeterone, hit a snag last summer when the drug failed in a phase 3 trial. The company laid off more than half its staff and stopped enrollment of a galeterone trial in patients with metastatic castration-resistant prostate cancer who have become resistant to the drug Xtandi.

While the large-molecule approach is promising, it has a couple of hurdles to overcome. The peptides tend to break down quickly, before they arrive at the target, while large molecules can’t pass through the cell membrane.

The University of Michigan researchers sidestepped the first issue by creating protein-like chains that were mirror images of the peptides. The team plans to create a 3D outline of how the peptides bind to ERG, with the goal of developing a small molecule that blocks ERG.

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