Diffuse gliomas are a leading cause of cancer-related death in people under 45 years old, with malignant brain tumors resulting in the greatest number of years of potential life lost in US adults. Modern large-scale genetic discovery has identified somatic molecular genomic alterations that can better classify these tumors. Recurrent isocitrate dehydrogenase (IDH) gene mutations are found in up to 20% of adult diffuse gliomas, identifying tumors with distinct etiology, associated genetic alterations, and overall natural history. As a result, IDH mutant gliomas have been newly-recognized as separate diagnostic entities within the 2016 World Health Organization Histological Classification. These gliomas are typically diagnosed in younger adults ranging from 20-50 years old, initially presenting as lower-grade lesions that can be responsive to standard-of-care treatments such as surgical resection, radiation and chemotherapy. However, these cancers inexorably progress to become higher-grade lesions, and prove fatal in most cases. New treatments are needed. In our prior work, we have shown that the altered metabolism within IDH1 mutant cells exposes the nicotinamide adenine dinucleotide (NAD+) biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) to selective inhibition with small molecules, resulting in profound genotype-specific metabolic vulnerabilities in IDH1 mutant cancer cells. Highlighting the central importance of NAD+ levels in IDH mutant gliomas, these observations strongly suggest that alternative strategies targeting NAD+ homeostasis may achieve substantial efficacy against these tumors. Herein, we propose to evaluate modulation of NAD+ steady-state levels in IDH mutant gliomas by multiple non-overlapping approaches, to identify unique dependencies, mediators of sensitivity and potential combinatorial therapeutic strategies. In addition, we plan to test innovative delivery methods which could minimize the toxicities associated with NAMPTi monotherapy, widening the therapeutic window for clinical translation. The successful completion of our proposed research will open new avenues for targeting the unique metabolic vulnerabilities of IDH1 mutant gliomas, translating into potential clinical therapies for patients with these tumors.
We propose to study the determinants of NAD+ metabolism in IDH mutant gliomas. Our application is relevant to the public health because IDH mutant gliomas are diagnosed in young adults, ages 20-50 years old, and there are no effective systemic therapies when surgery and radiation fail to offer durable disease control for these cancers. Relevant to the NCI mission, the objective of this study is to understand changes that are associated with sensitivity to specific metabolite perturbation, to inform strategies that can improve the efficacy of novel targeted therapies, with the goal to identify optimal therapeutic approaches for this disease.
|Shankar, Ganesh M; Kirtane, Ameya R; Miller, Julie J et al. (2018) Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A 115:E8388-E8394|
|Higuchi, Fumi; Fink, Alexandria L; Kiyokawa, Juri et al. (2018) PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide. Mol Cancer Ther 17:2551-2563|