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
Authors: Kaluzova Milota , Nasti Tahseen , Chen Hiao-Rong , Lowder Lindsey , Press Robert , Rosen Havi , Rupji Manali , Kallay Laura , Patel Rikesh , Burnham Andre , Xu Maxwell , Ross Alexandra , Keskin Havva , Connelly Erin , Izar Benjamin , Adamson Cory , Olson Jeffrey , Su Jing , Curran Walter , Kudchadkar Ragini , Schniederjan Matthew , Neill Stewart , Lawson David , Chan Michael , Kowalski Jeanne , Khan Mohammad , Krummel Daniel Pomeranz , Sengupta Soma 
Published: August 2019

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.
References 1. Akbani, et al. (The Cancer Genome Atlas Network, TCGA). Genome classification of cutaneous melanoma. Cell 2015; 161(7): 1681-1696. 2. Tirosh, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 2016; 352 (6282): 189-196.
Citation Format: Milota Kaluzova, Tahseen Nasti, Hiao-Rong Chen, Lindsey Lowder, Robert Press, Havi Rosen, Manali Rupji, Laura Kallay, Rikesh Patel, Andre Burnham, Maxwell Xu, Alexandra Ross, Havva Keskin, Erin Connelly, Benjamin Izar, Cory Adamson, Jeffrey Olson, Jing Su, Walter Curran, Ragini Kudchadkar, Matthew Schniederjan, Stewart Neill, David Lawson, Michael Chan, Jeanne Kowalski, Mohammad Khan, Daniel Pomeranz Krummel, Soma Sengupta. Identification of the GABAA receptor in melanoma brain metastases patient tumors and demonstration that it is a viable drug target using benzodiazepine-derivatives [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 247.