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Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research. [ABSTRACT FROM AUTHOR]

Purpose: Since the discovery of IDH mutations in glioma over a decade ago, significant progress has been made in determining how these mutations affect epigenetic, transcriptomic, and metabolic programs in brain tumor cells. In this article, we summarize current understanding of how IDH mutations influence DNA damage in glioma and discuss clinical implications of these findings. Methods: We performed a thorough review of peer-reviewed publications and provide an overview of key mechanisms by which IDH mutations impact response to DNA damage in gliomas, with an emphasis on clinical implications. Results: The effects of mutant IDH on DNA damage largely fall into four overarching categories: Gene Expression, Sensitivity to Alkylating Agents, Homologous Recombination, and Oxidative Stress. From a mechanistic standpoint, we discuss how mutant IDH and the oncometabolite (R)-2HG affect each of these categories of DNA damage. We also contextualize these mechanisms with respect to ongoing clinical trials. Studies are underway that incorporate current standard-of-care therapies, including radiation and alkylating agents, in addition to novel therapeutic agents that exert genotoxic stress specifically in IDH-mutant gliomas. Lastly, we discuss key unanswered questions and emerging data in this field that have important implications for our understanding of glioma biology and for the development of new brain tumor therapies. Conclusion: Mounting preclinical and clinical data suggest that IDH mutations alter DNA damage sensing and repair pathways through distinct mechanisms. Future studies are needed to deepen our understanding of these processes and provide additional mechanistic insights that can be leveraged for therapeutic benefit. [ABSTRACT FROM AUTHOR]

Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models. [ABSTRACT FROM AUTHOR]