Mutação IDH1R132H em glioblastoma como alvo terapêutico

Abstract

Driver mutations in Isocitrate Dehydrogenase 1 (IDH1) are present in 70-80% of grade II and III gliomas, which the majority eventually progress to glioblastoma multiforme (GBM). In this molecularly distinct class of malignant gliomas, mutant IDH1 enzyme produces 2-hydroxyglutarate (2-HG), an "oncometabolite" that inhibits ±-ketoglutarate dependent histone and DNA demethylases resulting in characteristic hypermethylation of genomic DNA and suppression of cellular differentiation. Therefore, this oncometabolite integrates oncogenic signaling, metabolism and transcription. We have demonstrated the preclinical efficacy and mechanism of action of the FDA approved DNA demethylating drug 5-azacytidine. In molecularly accurate models, systemic 5-azacytidine administration reduces tumor burden, extends survival and induce differentiation in vivo. The focus of this study is to understand the mechanism of DNA demethylation therapy for the treatment of IDH1 mutant glioma using our patient derived model of IDH1 mutant anaplastic astrocytoma and additional models of IDH1 mutant grade III oligodendroglioma and oligoastrocytoma. We propose to demonstrate the mechanism and efficacy of 5-azacytidine induced tumor regression in vitro and in vivo using orthotopic IDH1 mutant glioma systems. To confirm the in vivo mechanism we will study target inactivation, differentiation, and key alterations in transcription and methylation. In addition, we will test the synergistic benefit of combining 5-azacytidine with the current standard of care for high grade gliomas and assess the mechanism of tumor regression in these tumors including alterations in apoptosis and differentiation. Overall, our goal is to elucidate the mechanism of 5-azacytidine induced tumor regression in IDH1 mutant tumors. Our preliminary results are promising, but synergistic combinations as well as a more in-depth and mechanistic approach is needed to increase the chances that the work will translate successfully to the clinic. The results from this work will allow us to better design and possibly support a new trial for patients with IDH1 mutant glioma, which account for a substantial fraction of brain cancer mortality. (AU)