Approximately half of melanoma skin cancers carry activating mutations in the BRAF oncogene, leading to activation of the Mitogen Activated Protein Kinase (MAPK) pathway. Inhibition of the BRAF oncoprotein with targeted drugs provides substantial benefit to patients, albeit that most patients ultimately relapse with resistant disease. We identified that such drug-resistant cancer cells have acquired a new vulnerability that was not present in the original drug-sensitive cancer cells. More importantly, we found as part of my ERC advanced grant subsidy, that drug-resistant melanoma cells have acquired sensitivity to a class of drugs known as histone deacetylase (HDAC) inhibitors, such as vorinostat. The purpose of this "proof of concept" study was to test in a limited number of patients whether vorinostat can selectively kill BRAF-inhibitor resistant cancer cells, leaving only drug-sensitive tumor cells in the patient that can we re-treated with the BRAF inhibitor drug.
The clinical trial named "HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma" opened at the Antoni van Leeuwenhoek hospital on July 19, 2016. The trial is registered under ClinicalTrials.gov identifier NCT02836548.
At the date of the final report, six patients have been enrolled in this trial and their responses were analyzed. Biopsies were taken before and after vorinostat therapy to assess the prevalence of BRAF inhibitor resistant cells in the patients tumor.
We were able to perform a conclusive analysis on three before and after vorinostat biopsy pairs from three patients. Molecular analyses of these biopsies revealed that prior to vorinostat treatment, as expected, there was an abundance of BRAF inhibitor resistant cells in the patients tumor, but these cells were either severely reduced (1 patient) or completely undetectable (2 patients) after only 4 weeks of vorinostat therapy. No major adverse events were seen in any of the patients treated with vorinostat at the dose of 360 mg daily used in this trial.
We conclude from the proof of concept study that vorinostat can be a potentially effective therapy for BRAF inhibitor resistant melanoma. Based on this study, we will engage in a larger follow up study to further test the clinical use of vorinostat in drug resistant melanoma.
