Attacking treatment-resistant prostate cancer by blocking its stress response

Prostate cancer cells rely on protein synthesis to fuel their growth, but there can be too much of a good thing: Prostate tumors that are flooded with protein will actually die. Research has shown that treatment-resistant prostate cancer has a built-in stress response—an automatic brake that prevents protein synthesis from getting out of control and killing the cancer cells. Now researchers at the University of California, San Francisco, are figuring out how to interfere with that brake so prostate-cancer cells will set off on a path to self-destruction.

The scientists focused their attention on two genetic mutations seen in half of patients with treatment-resistant prostate cancer. One mutation activates the cancer-causing gene MYC, while the other disables PTEN, a tumor suppressor. They discovered that aggressive prostate tumors with both mutations have low rates of protein synthesis, and they traced that anomaly to a specific protein called P-eIF2a, which dials down overall protein production in cells.

From there, they went on the hunt for a compound that could block P-eIF2a. They found it in an unlikely place: a UCSF lab that’s studying severe brain damage. A compound called ISRIB, which was developed in that lab, prevents P-eIF2a from doing its job, they discovered. They reported their findings in the journal Science Translational Medicine.

"We have discovered the molecular restraints that let cancer cells keep their addiction under control and showed that if we remove these restraints they quickly burn out under the pressure of their own greed for protein," said senior author Davide Ruggero, Ph.D., professor of urology and cellular and molecular pharmacology at UCSF, in a statement.

More than 1 in 10 men will be diagnosed with prostate cancer at some point in their lives, and 1 in 41 will die of the disease, making it the second leading cause of cancer death in American men, according to the American Cancer Society. Aggressive prostate tumors often respond to hormone therapy, but most become resistant to that, too.

Several companies and academic research centers are pursuing new technologies aimed at combating aggressive prostate cancer. Tmunity Therapeutics, for example, is working on a CAR-T treatment for prostate cancer and recently pulled in a $100 million series A to help fund that research. The rise of DNA sequencing has pointed to several new targets in the disease, including mutations in BRCA1 and BRCA2 that could open up the possibility of treating aggressive cases with PARP inhibitors.

To test the potential of ISRIB, the UCSF researchers implanted cells from a prostate cancer treatment into mice and showed they could shrink the tumors with the drug. ISRIB also extended survival, they reported, and normal cells were unaffected. They believe the findings should be used to design trials of ISRIB in patients with aggressive prostate tumors.

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