Mutant protein linked to ovarian cancer could be new treatment target

By Allen Cone

March 28 (UPI) -- Researchers have found a mutant protein that is linked to ovarian cancer growth, prompting the possibility of new drugs to target this regulator.

Researchers at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center in Houston studied a previously unknown cellular pathway that selectively regulates a mutant protein called p53-R175H. Their findings were published Tuesday in Nature Communications.


"Our findings offer a new opportunity for regulating mutant p53-R175H by developing drugs that inhibit USP15," senior author Dr. JoAnne Richards, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor, said in press release. "A possible future scenario in the clinic could be to use DNA analysis to determine whether this p53 mutation is present in a patient's tumor. If so, then we may use our approach to treat it or combine it with other anticancer drugs and take advantage of the fact that treatment with inhibitors of USP15 results in the cancer cells becoming more susceptible to chemotherapy."


Among women, ovarian cancer is the fifth-leading cause of cancer death, according to the Centers for Disease Control and Prevention. Although it accounts for only about 3 percent of all cancers in women, it causes more deaths than any other cancer of the female reproductive system.

The cancer is now treated with surgery and chemotherapy.

"Chemotherapy for ovarian cancer is based on drugs that act on any cell that is rapidly dividing, healthy or malignant, which has side effects," said Dr. Achuth Padmanabhan, a researcher and instructor of molecular and cell biology at Baylor College of Medicine. "If we are able to develop treatments that target only cancer cells, then we might be able to minimize side effects."

Among high-grade serous ovarian carcinomas, more than 96 percent have mutations in the p53 gene. The mutations play key roles in the production of tumors and in the development of drug resistance.

"Normal p53 is rapidly broken down inside most healthy cells, but p53 mutants such as p53-R175H, are not. They form very stable protein clusters inside cells that promote cancer and induce drug resistance," Padmanabhan said. "Researchers have discovered that if we remove the mutant p53 forms from cancer cells, the cells will enter a path toward cell death and become more sensitive to chemotherapy. This is very valuable from the clinical point of view."


The researchers decided to find ways to reduce the levels of p53-R175H inside cancer cells and their eventual destruction, discovering a method of regulating mutant p53, but not the normal form of the protein -- which Padmanabhan said could also lead to cancer.

In experiments, researchers tested a small molecule called MCB613 based on its ability to treat ovarian cancer in mice. They found the molecule reduced levels of p53-R175H in ovarian cancer cells, but not in the healthy ones, by reducing levels of another protein called USP15 rather than interacting with the mutant protein on its own.

Researchers also found that mutant p53-R175H is more sensitive to ovarian steroids, leading to a potential two-prong treatment for the cancer.

"We are combining ways of regulating steroid receptor and coactivator action, as well as p53," said study co-author Dr. Bert O'Malley, associate director of basic research in the Comprehensive Cancer Center. "Maybe by manipulating both of those pathways we may have a better chance of regulating cancer growth."

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