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Newly identified pathway provides target for ovarian cancer treatment
Reuters Health News
April 12, 2018
A newly identified cellular pathway provides a possible target for treatment of ovarian and other cancers, researchers report.
"USP15 is a 'druggable' selective upstream regulator of the clinically important p53-R175H mutant," Dr. Achuth Padmanabhan from Baylor College of Medicine, in Houston, Texas, told Reuters Health by email. "By targeting USP15, we can potentially cause selective killing of ovarian cancer cells that carry p53-R175H mutation."
Mutations in p53 are present in more than 50% of human malignancies. Gain-of-function mutants, such as p53-R175H, form stable aggregates that accumulate in cells and contribute to carcinogenesis and drug resistance.
Dr. Padmanabhan and colleagues now report a previously unknown pathway that selectively regulates the p53-R175H mutant protein.
A small-molecule compound called MCB-613, previously characterized as a steroid receptor coactivator (SRC) "super" stimulator, caused a rapid and sustained decrease in the level of p53-R175H in an ovarian cancer cell line. This effect was independent of SRC in these cells.
MCB-613 treatment caused rapid ubiquitination and turnover of p53-R175H, the researchers report in Nature Communications, online March 28.
Blockage of USP15, a deubiquitinase (DUB) enzyme that is amplified in several cancers, resulted in decreased levels of p53-R175H in ovarian cancer cells and, in separate experiments, reduced the viability of such cells expressing the p53-R175H mutant.
"Here, we show that USP15 is a selective upstream regulator of p53-R175H mutant protein," Dr. Padmanabhan said. "If we deplete USP15 levels or inhibit its activity, we can cause degradation of p53-R175H mutant selectively and cause ovarian cancer cells containing this mutation to undergo cell death. What this means is, this discovery has the potential to pave the way for a personalized therapeutic option for ovarian cancer based on the p53 mutation status of the patient's tumor."
"Such an advance will be a huge leap in the treatment options currently available for ovarian cancer," he said.
USP15 expression is also amplified in lobular breast carcinomas, prostate cancer, cervical squamous cell carcinomas, and glioblastoma, suggesting that USP15 might prove to be a therapeutic target in other cancers.
Dr. Kwang-Hyun Baek from CHA University, in Gyeonggi-Do, Korea, who has investigated the role of DUBs in various signaling pathways, told Reuters Health by email, "Since depletion of gain-of-function (GOF) oncogenic p53 mutant protein (p53-R175H) via protein degradation leads to tumor regression, high therapeutic potential for small DUB inhibitor molecules in ovarian cancer can be obtained, reflecting that the regulation of proteolytic degradation provides effective personalized treatment of cancer patients."
"A number of proteolytic DUB inhibitor molecules have been developed to treat cancer effectively and efficiently," said Dr. Baek, who was not involved in the new research. "Even though it is a bit early to consider these molecules as effective drugs for cancer therapy, they should be developed and evolved to treat cancer patients in coming years due to the importance of protein stability."
"Validation of molecular mechanisms mediated by this inhibitor in living organisms should help to develop anti-cancer drug molecules," Dr. Baek said.
"We are excited about these findings and are working towards extending these studies to preclinical models," Dr. Padmanabhan said.
—Will Boggs, MD