Purpose of Review: Low-grade gliomas (LGG) are a group of primary brain tumors that arise from supporting glial cells. They are characterized by a mutation in the isocitrate dehydrogenase (IDH) enzyme and include astrocytomas and oligodendrogliomas. They usually affect young adults, and their main treatment consists of surgical resection, followed by radiation and chemotherapy in selected patients. This article reviews recent research on the clinical and molecular aspects of the disease and innovative therapeutic modalities in the process. Recent Findings: Newly identified clinical and molecular features are currently used in the classification of LGG and applied in treatment-planning decisions. Advanced studies on the cellular level have an advanced understanding of the metabolic effects induced by IDH mutations, offering opportunities for specific targeted therapies that may improve patient outcomes. Such findings may lead to a paradigm shift in the treatment of these tumors. Summary: Although LGG are sensitive to radiation and chemotherapy, these therapies are not curative, and patient survival remains limited, raising the need for more creative and effective interventions.

NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation. Significance: Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit. See related commentary by Pirozzi and Yan, p. 1629. This article is highlighted in the In This Issue feature, p. 1611

Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct subtype, reflected in the World Health Organization (WHO) 2016 revised diagnostic criteria. To inform IDH-targeting trial design, we sought to characterize outcomes exclusively within IDH mutant gliomas. We retrospectively analyzed 275 IDH mutant glioma patients treated at our institution. Progression was determined using low-grade glioma criteria from Response Assessment in Neuro-Oncology. We calculated survival statistics with the Kaplan-Meier method, and survival proportions were correlated with molecular, histologic, and clinical factors. During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression (PFS1) events (54.1%) were observed. Median PFS1 was 5.7 years (95% CI: 4.7-6.4) and OS was 18.7 years (95% CI: 12.2 y-not reached). Consistent with prior studies, we observed an association of grade, molecular diagnosis, and treatment with PFS1. Following the first progressive episode, 79 second progression events occurred during a median follow-up period of 4.1 years. Median PFS following an initial progressive event (PFS2) was accelerated at 3.1 years (95% CI: 2.1-4.1). PFS2 was a surrogate prognostic marker, identifying patients with poorer overall survival. We report outcomes in a large cohort of IDH mutant glioma, providing a well-characterized historical control population for future clinical trial design. Notably, the interval between first and second recurrence (PFS2, 3.0 y) is shorter than time from diagnosis to first recurrence (PFS1, 5.7 y), evidence that these tumors clinically degenerate from an indolent course to an accelerated malignant phase. Thus, PFS2 represents a relevant outcome for trials investigating drug efficacy at recurrence.

Purpose: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. Experimental Design: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. Results: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1^R132H and 1p/19q codeletion) and PIK3CA^E542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. Conclusions: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.