A new combination therapy inhibits tumor growth and blocks drug-induced resistance in ovarian cancer

A new combination therapy inhibits tumor growth and blocks drug-induced resistance in ovarian cancer

A pairing of two experimental drugs inhibits and blocks tumor growth, according to a preclinical study led by Weill Cornell Medicine researchers led by Weill Cornell Medicine physicians. The research demonstrates a promising strategy against this difficult-to-treat malignancy and generally demonstrates a powerful new approach for identifying 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 inCell Reports MedicineThe researchers applied a new precision medicine approach that focused not on individual mutations but on activating growth signaling pathways specific to ovarian tumor cells. Using these 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 are excited about the potential to use this combination in ovarian cancer and we believe this approach will be useful for identifying effective treatments against other cancers that do not contain highly recurrent targetable mutations. “

Dr. Benjamin Hopkins, senior author, assistant professor of research in physiology and biophysics and member of the Engländer Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine

The first author of the study was Dr. Shalini Nath, a postdoctoral researcher at the English Institute.

According to the National Cancer Institute, nearly 250,000 women in the United States are living with ovarian cancer, and there are around 20,000 new cases each year. Standard treatment includes 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 data sets in ovarian tumor samples to show that, despite their diversity, the mutations underlying these cancers usually lead to the hyperactivity of a cell growth pathway called the MAPK pathway. In screening a range of drug compounds for growth burning effects in 32 different cell models of human cancers, they found that an experimental drug called RigoStib, which targets the MAPK pathway and is being tested against other cancer types, had improved efficacy against ovarian cancer. Although RigoStib inhibits the MAPK pathway, the team's experiments showed that in ovarian tumor cells this has the effect of partially repressing the PI3K/mTOR pathway.

The team therefore conducted a second round of screening, this time using combinations of rigosertib and various PI3K/mTOR inhibitors - the idea being to target tumors more effectively by blocking both the MAPK and PI3K/mTOR pathways. They found that in preclinical models, although rigosertib stands up alone to standard platinum-based chemotherapy and combines it with a PI3K/mTOR inhibitor, it works even better in preclinical models.

Dr. Hopkins hopes these results will stimulate drug developers' interest in this approach, which could include candidate drugs that behave like RigoSertib but are more effective.

“We are also working to identify more of these tumor-specific dependencies of ovarian cancer, which could provide further options for second-line therapy, because there are currently no second-line curative therapies for this cancer,” he said.

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