Scientists find a possible new target for metastatic prostate cancer

MYC is an oncogene that’s linked to many cancer types, including prostate cancer. But it’s a notoriously undruggable target. Now, a team led by scientists at Cold Spring Harbor Laboratory has found a way to indirectly control MYC, which they believe could offer a new strategy for treating metastatic prostate cancer.

The same team previously found that a loss of function of the gene PHLPP1 could activate a protein kinase called Akt that regulates cell survival. That triggers abnormal cancer-like tissue growth in the prostate. This time, they were surprised to discover that a close relative, a protein called PHLPP2, helps metastatic prostate cancer cells survive and spread.

They described their discovery in the Journal of Cell Biology.

PHLPP2 is a phosphatase enzyme that can change the structure of proteins and thereby their functions. While the loss of the PHLPP1 gene activates Akt during the formation of prostate cancer, once it metastasizes, Akt is suppressed by a mechanism that requires PHLPP2, the team found.

Specifically, in mouse-derived cells, PHLPP2 deletion caused a sharp reduction in levels of MYC. The PHLPP2 enzyme helps stabilize MYC by removing a phosphate group, which would otherwise degrade MYC, according to the team.

To further test their theory, the researchers, led by Cold Spring Harbor Laboratory scientist Lloyd Trotman, used a mouse model of metastatic prostate cancer. Mice which had the PHLPP2 gene knocked out showed significantly reduced tumor metastasis to other organs, they found.

Then, Trotman and colleagues treated human prostate cancer cells with a drug called NCI45586, which they obtained from a library of the National Cancer Institute. The drug inhibits PHLPP2. A dose-dependent reduction in total MYC protein was observed, and that also translated into cancer cell death.

Metastatic prostate cancer has a five-year survival rate of only 28%, but when the disease is confined to the prostate, that rate is nearly 99%, Trotman said in a statement.

RELATED: New 'peptoids' show promise in resistant prostate cancer

Scientists are exploring other strategies to improve the life expectancy of patients with the difficult-to-treat metastatic form of the disease. A multidisciplinary team from New York University, for example, developed a novel drug that targets a mutation in the Wnt signaling pathway that's attributed to about 20% of castration-resistant prostate cancer. The drug, called a peptoid, is designed to block the interaction between beta catenin protein—which accumulates after Wnt activation—and a T-cell factor that promotes cell proliferation.

California-based Harpoon Therapeutics is developing T cell-engaging bispecific antibodies that redirect T cells to attack tumor cells. It recently raised $70 million in a series C to help fund phase 1 testing of its lead drug, HPN424, in metastatic castration-resistant prostate cancer. The drug targets a prostate membrane antigen that’s highly expressed in mCRPC.

Trotman and colleagues argue that their study offers proof of principle “that targeted efforts for designing PHLPP2 inhibitors could result in very efficient new drugs that suppress MYC-driven cancer,” they wrote. The PHLPP2 enzyme is an attractive drug target, because blocking it doesn’t seem to interrupt any essential functions in healthy cells, they said.

The findings could eventually lead to new therapies for other cancers, they added. “It is estimated that 450,000 Americans are diagnosed each year with a cancer that is driven by MYC,” the study’s first author Dawid Nowak said in a statement.