A pairing of two experimental drugs inhibits tumor growth and blocks drug-induced resistance in ovarian cancer, according to a preclinical study led by Weill Cornell Medicine investigators. The research reveals a promising strategy against this hard-to-treat malignancy, and more generally demonstrates a powerful new approach for the identification of effective regimens to treat genetically diverse cancers.
Ovarian cancer is genetically diverse in the sense that it can be driven by mutations in many different genes. This complicates the standard strategy of developing drugs to target common driver mutations. In the study, published July 7 in Cell Reports Medicine, the researchers applied a new precision medicine approach focused not on individual mutations but instead on the activation of growth signaling pathways specific to ovarian tumor cells. Using this pathway level data, they identified a new combination treatment strategy that selectively targets ovarian tumor cells and reduces ovarian tumor growth in preclinical models.
"We're excited by the potential of using this combination in ovarian cancer, and we think this approach will be useful to identify effective treatments against other cancers that don't contain highly recurrent targetable mutations," said study senior author Dr. Benjamin Hopkins, an assistant professor of research in physiology and biophysics and a member at the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
The study's first author was Dr. Shalini Nath, a postdoctoral research associate at the Englander Institute.
According to the National Cancer Institute, nearly 250,000 women are living with ovarian cancer in the United States, and there are roughly 20,000 new cases each year. Standard treatment involves surgery to remove the ovaries followed by chemotherapy, but recurrence is common, and the five-year survival rate is only about 50%. In general, oncologists recognize that they need better treatment options.
Dr. Hopkins and his team analyzed existing datasets on ovarian tumor samples to show that, despite their diversity, the mutations underlying these cancers commonly lead to the hyperactivity of a cell-growth pathway called the MAPK pathway. Screening a set of drug compounds for growth-slowing effects in 32 different cell models of human cancers, they found that an experimental drug called rigosertib, which targets the MAPK pathway and is being tested against other cancer types, showed enhanced efficacy against ovarian cancer. Though rigosertib inhibits the MAPK pathway, the team's experiments showed that in ovarian tumor cells this has the effect of partially de-repressing the PI3K/mTOR pathway—a mechanism of treatment resistance.
The team therefore did a second round of screening, this time with combinations of rigosertib and different PI3K/mTOR inhibitors—the idea being to hit tumors more effectively by blocking both the MAPK and PI3K/mTOR pathways. They found that although rigosertib on its own outperforms standard platinum-based chemotherapy in preclinical models, combining it with an PI3K/mTOR inhibitor works even better.
Dr. Hopkins hopes that these results will spur drug developers' interest in this approach, which could include candidate drugs that that act like rigosertib but are more potent.
"We're also working to identify more of these tumor specific dependencies in ovarian cancer that could offer further options for second-line therapy—because currently there are no curative second-line therapies available for this cancer," he said.
