Abstract 247: Identification of the GABAA receptor in melanoma brain metastases patient tumors and demonstration that it is a viable drug target using benzodiazepine-derivatives

Abstract

Abstract Primary cutaneous melanoma is often successfully treated in early stages in patients with regional disease. While distant metastatic disease, including brain metastasis, that develops in most stage IV melanoma patients, carries a particularly poor prognosis with median overall survival of only 4-5 months. Standard-of-care treatment of brain metastases includes surgery, radiation, and chemotherapy. The fact that melanoma is a radio-resistant cancer, significantly limits treatment options for melanoma that has metastasized to the brain. There is clearly a significant demand for new therapeutic approaches. We have conducted a whole transcriptomic analysis of melanoma brain metastases to provide insight into molecular changes that may contribute to metastasis as well as to identify potential therapeutic targets in the metastasized cancer. Total RNA was extracted from 29 formalin-fixed paraffin-embedded (FFPE) melanoma brain metastatic samples, libraries constructed and enriched for transcript fragments with coding regions. Libraries were subjected to Transcriptome Capture (TCap) targeting 21,415 genes, which represents more than 98% of the total RefSeq exome. Sequencing was performed on the Illumina HiSeq platform. Gene expression analysis of melanoma brain metastatic samples reveals high expression levels of ion channels, including subunits of the ligand-gated neurotransmitter GABAA receptors. We will present differential expression analysis between recent melanoma transcriptomic studies [1, 2] and melanoma brain metastases samples. More than 20% of FDA approved drugs target ion channels. We report that repurposing of one such class of drugs targeting GABAA receptors can impair melanoma cell viability in vitro and reduce tumor volume in vivo. GABAA receptors can serve as a potential therapeutic target for treatment brain metastasis.