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Androgen receptor (AR) gene is mapped to Xq11-12. It functions as a steroid-hormone-activated-transcription-factor. AR splice variants lacking the Ligand-Binding-Domain (LBD), such as AR-V7/AR3, which arise primarily through exon skipping and cryptic exon inclusion, are activated in a ligand-independent mechanism. The association between sex steroid receptors and brain tumors was described since 1983, but in contrast to the well-established oncogenic role played by androgen receptor (AR) in prostate cancer and the growing evidences on its role in breast cancer, the expression and significance of AR in GBM is controversial and poorly studied. Our previous presented data (Lavon, I. et al. CSIG-13. Neuro-Oncology 18, vi43-vi43 (2016)) and our current results have demonstrated for the first time amplification of AR at the DNA, RNA and protein levels in the majority of GBM samples in patients of both sexes. Our AR-RNA expression results were validated in 703 glioblastomas by analysis of several datasets including the TCGA. We also showed that 30% of glioblastomas express the constitutively active AR-splice-variant AR-V7/AR3. Based on the previously reported activation of AR-V7/AR3 by RTKs, including EGFR, we identified that combination therapy with the AR-antagonist Enzalutamide and EGFR inhibitor is more effective than AR-antagonists alone in cell line expressing AR-V7/AR3. A cell cycle analysis of glioma cells treated with Enzalutamide demonstrated a dose-dependent number of cells in sub-G1 phase suggesting apoptosis as the mechanism for cell death. Enzalutamide given orally (20 mg/kg three time per week) to nude mice bearing human gliomas (U78MG) resulted in reduction of 72% in tumor volume (p=0.0027) as compared to mice treated with vehicle. We hope that the results of this study together with continued laboratory efforts will lead to a new approach for the treatment of human glioblastoma.

Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function.