Nivolumab, ipilimumab duo effective in poor prognosis advanced melanoma patients
Since around half the cases of malignant melanoma are driven by mutation in the BRAF gene, the team focused on combinations that might address intrinsic resistance to the BRAF inhibitor vemurafenib. They found that combining that drug with the cediranib, an investigational drug that targets a group of proteins known to be involved in blood vessel formation, had synergistic effects against cell lines that were resistant to treatment with vemurafenib alone but not those sensitive to single-agent therapy. They also tested this combination in animal models into which two resistant cell lines had been grafted, and found significant synergistic effects against both tumor models.
"We need to confirm this synergistic activity of vemurafenib and cediranib across a broader range of melanoma models, investigate why the particular combination is effective, and find biomarkers that predict which patients with BRAF-mutant melanoma should receive this combination," says Friedman, who is a research fellow in Dermatology at Harvard Medical School. "What is really exciting is that these drugs are already in the clinic; in fact a clinical trial for a similar combination is already underway at another research center. We may be able to quickly improve on the selection criteria for this trial and identify patients whose tumors might respond."
He adds, "This study was actually a pilot project for a much larger effort within the Center for Molecular Therapeutics to map responses against drug combinations across hundreds of cancer cell lines, not just melanoma, and look for novel combinations that will benefit subsets of patients regardless of the particular type of tumor they have. Since our collection of cell lines is completely genetically annotated - which means that mutations and expression changes in each line's genes have been documented - we should be able to identify in advance patients who will benefit from specific combinations. Beyond the specific combination we focused on, this study should help others understand the technical challenges of analyzing such a large combination dataset."