Researchers have discovered a biomarker that could help predict whether patients with melanoma harboring mutations in the BRAF gene are likely to respond to BRAF-targeted treatment. The discovery could help speed up treatment decisions, say the researchers.
They presented their findings at the 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19-23 in Boston, MA.
About 50% of melanomas have mutations in the BRAF gene, and there are two federally approved drugs in the US that target BRAF for treating such cancers.
However, not all patients whose melanomas contain BRAF mutations respond to these BRAF-targeted drugs, and most of those who do, eventually relapse as the cancer becomes resistant to the drugs’ effects.
Dr. Ryan Corcoran, a clinical investigator and assistant professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, says:
“Our study has identified decreased phosphorylation of the protein S6 after treatment with BRAF-targeted drugs as a functional biomarker that predicts sensitivity of BRAF-mutant melanomas to these drugs.”
He explains that they have also developed a minimally invasive way to quickly find out if these changes are happening in patients’ tumors after treatment.
Dr. Corcoran says:
“As a result, we think that we can quickly determine whether or not a patient is likely to respond to a BRAF-targeted drug and help speed up treatment decisions, although we need to verify this in larger clinical studies.”
Cancers occur when cells go awry. Many of the problems that arise are caused by gene mutations that lead to inappropriate activity of the proteins they code for.
For their investigation, the researchers compared differences in this “downstream” protein activity in BRAF-mutant melanoma cell lines responsive and resistant to the BRAF-targeted drug vemurafenib.
They discovered that BRAF-mutant melanoma cell lines responsive to treatment with vemurafenib showed “decreased phosphorylation” in the protein S6. They found this also to be the case when they tested the effect in mice.
To confirm their findings, they then looked for this same effect in tumor biopsies from nine patients with BRAF-mutant melanomas before and after they had started treatment with a BRAF-targeted drug.
They found six of the patients showed lowering of S6 phosphorylation in their tumor cells in response to treatment, and this was linked to a nearly five-fold improvement in progression-free survival.
In a final stage of the study, the team developed a way to rapidly find out if S6 phosphorylation was changing in tumor cells.
They tested a way to do this in real time, requiring only fine-needle aspiration biopsies taken before and during the first two weeks of treatment with a BRAF-targeted drug.
The tests showed that a decrease in S6 phosphorylation after treatment correlated with treatment response.
S6 phosphorylation is the end result of many signaling pathways in different types of cancer – BRAF is just one of them.
So the team is now investigating whether this change in the protein could be a biomarker of response to treatments that target these pathways in other cancers.
A Damon Runyon Clinical Investigator Award, funds from the National Institutes of Health and the National Cancer Institute helped finance the study.
Earlier this year, using DNA sequencing, researchers in the UK reported discovering possible new treatment targets for mucosal melanoma, a rare form of cancer.