Use, access, and initial outcomes of off-label ivosidenib in patients with IDH1 mutant glioma.

Background: Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Methods: Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. Results: The cohort age range was 21-74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Conclusions: Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.

Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.

PURPOSE: We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. PATIENTS AND METHODS: One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. RESULTS: In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). CONCLUSION: Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

Recombinant polio-rhinovirus immunotherapy for recurrent paediatric high-grade glioma: a phase 1b trial.

BACKGROUND: Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric high-grade glioma and has shown promise in adults with recurrent glioblastoma. The poliovirus receptor CD155 is ubiquitously expressed in malignant paediatric brain tumours and is a treatment target in paediatric high-grade glioma. We aimed to assess the safety of lerapolturev when administered as a single dose intracerebrally by convection enhanced delivery in children and young people with recurrent WHO grade 3 or grade 4 glioma, and to assess overall survival in these patients. METHODS: This phase 1b trial was done at the Duke University Medical Center (Durham, NC, USA). Patients aged 4-21 years with recurrent high-grade malignant glioma (anaplastic astrocytoma, glioblastoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic pleomorphic xanthoastrocytoma) or anaplastic ependymoma, atypical teratoid rhabdoid tumour, or medulloblastoma with infusible disease were eligible for this study. A catheter was tunnelled beneath the scalp for a distance of at least 5 cm to aid in prevention of infection. The next day, lerapolturev at a dose of 5 × 107 median tissue culture infectious dose in 3 mL infusate loaded in a syringe was administered via a pump at a rate of 0·5 mL per h as a one-time dose. The infusion time was approximately 6·5 h to compensate for volume of the tubing. The primary endpoint was the proportion of patients with unacceptable toxic effects during the 14-day period after lerapolturev treatment. The study is registered with ClinicalTrials.gov, NCT03043391. FINDINGS: Between Dec 5, 2017, and May 12, 2021, 12 patients (11 unique patients) were enrolled in the trial. Eight patients were treated with lerapolturev. The median patient age was 16·5 years (IQR 11·0-18·0), five (63%) of eight patients were male and three (38%) were female, and six (75%) of eight patients were White and two (25%) were Black or African American. The median number of previous chemotherapeutic regimens was 3·50 (IQR 1·25-5·00). Six of eight patients had 26 treatment-related adverse events attributable to lerapolturev. There were no irreversible (ie, persisted longer than 2 weeks) treatment-related grade 4 adverse events or deaths. Treatment-related grade 3 adverse events included headaches in two patients and seizure in one patient. Four patients received low-dose bevacizumab on-study for treatment-related peritumoural inflammation or oedema, diagnosed by both clinical symptoms plus fluid-attenuated inversion recovery MRI. The median overall survival was 4·1 months (95% CI 1·2-10·1). One patient remains alive after 22 months. INTERPRETATION: Convection enhanced delivery of lerapolturev is safe enough in the treatment of recurrent paediatric high-grade glioma to proceed to the next phase of trial. FUNDING: Solving Kids Cancer, B+ Foundation, Musella Foundation, and National Institutes of Health.

Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With or Without Radiation Therapy: A 25-Year Retrospective Analysis of a Single-Institution Experience.

Purpose: Atypical (World Health Organization [WHO] grade 2) and malignant (WHO grade 3) meningiomas have high rates of local recurrence, and questions remain about the role of adjuvant radiation therapy (RT) for patients with WHO grade 2 disease. These patients frequently require salvage therapy, and optimal management is uncertain given limited prospective data. We report on the long-term outcomes for patients with atypical and malignant meningiomas treated with surgery and/or RT at our institution. Methods and Materials: Data were collected through a retrospective chart review for all patients with WHO grade 2 or 3 meningiomas treated with surgery and/or RT at our institution between January 1992 and March 2017. Progression-free survival (PFS) and overall survival (OS) were described using the KaplanMeier estimator. The outcomes in the subgroups were compared with a log-rank test. A Cox proportional hazards model was used for the univariable and multivariable analyses of predictors of PFS. Results: A total of 66 patients were included in this analysis. The median follow-up was 12.4 years overall and 8.6 years among surviving patients. Fifty-two patients (78.8%) had WHO grade 2 meningiomas, and 14 patients (21.2%) had WHO grade 3 disease. Thirty-six patients (54.5%) were treated with surgery alone, 28 patients (42.4%) with surgery and adjuvant RT, and 2 patients (3%) with RT alone. Median PFS and OS were 3.2 years and 8.8 years, respectively. PFS was significantly improved with adjuvant RT compared with surgery alone (hazard ratio, 0.36; 95% confidence interval, 0.18-0.70). Patients with Ki-67 index >10% showed a trend toward worse PFS compared with patients with Ki-67 ≤10% (hazard ratio, 0.51; 95% confidence interval, 0.25-1.04). No significant differences in PFS or OS were observed with respect to Simpson or WHO grade. Conclusions: For patients with atypical or malignant meningiomas, adjuvant RT was associated with significantly improved PFS, and Ki-67 index >10% was associated with a trend toward worse PFS. Given the long-term survival, high recurrence rates, and efficacy of salvage therapy, patients with atypical and malignant meningiomas should be monitored systematically long after initial treatment.

Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial.

PURPOSE: At diagnosis and throughout the disease course, patients with high-grade glioma (HGG) experience a diminished quality of life (QOL) and increased fatigue. Naltrexone, an orally semisynthetic opiate antagonist, is FDA-approved for the treatment of heroin/alcohol addiction, and low-dose naltrexone (LDN) has been observed to improve QOL and lower fatigue in other neurological illnesses, such as multiple sclerosis. LDN is believed to function as a partial agonist and can lead to shifts in neurochemicals that reduce fatigue. Based on this, we sought to study whether LDN has an impact on QOL and fatigue in patients with HGG. METHODS: In a placebo-controlled, double-blind study, we randomized 110 HGG patients to receive placebo (N = 56) or LDN 4.5 mg orally at night (N = 54). Subjects received LDN or placebo at day 1 of concurrent radiation and temozolomide therapy and continued for 16 weeks. Change from baseline in patient-reported outcomes of QOL (Functional Assessment of Cancer Therapy-Brain) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) was assessed. RESULTS: Demographics were WHO grade IV (85%), male (56%), KPS 90-100 (51%), grossly resected (55%), and mean age of 56 years. QOL and fatigue changes between baseline and post concurrent chemotherapy and radiation therapy were not significantly different between patients receiving LDN or placebo. The adverse event profiles for LDN and placebo were similar and attributed to concomitant use of temozolomide. CONCLUSIONS: LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy. TRIAL REGISTRATION: United States National Library of Medicine Clinical Trials.gov NCT01303835, Date 2/25/2011.

Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.

Purpose: To describe our population of primary brain tumor (PBT) patients, a subgroup of cancer patients whose intensive care unit (ICU) outcomes are understudied. Methods: Retrospective analysis of PBT patients admitted to an ICU between 2013 to 2018 for an unplanned need. Using descriptive analyses, we characterized our population and their outcomes. Results: Fifty-nine PBT patients were analyzed. ICU mortality was 19% (11/59). The most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies. Further study of a larger population would inform guidelines for triaging PBT patients who would most benefit from ICU-level care.

Lay abstract Purpose: Data are lacking regarding outcomes of patients with primary brain tumors (PBTs) admitted to an intensive care unit (ICU), which may it difficult for ICU providers to know who of these patients will best benefit from ICU-level care. We aimed to describe our patient population to contribute to the limited data. Methods: We performed a retrospective analysis of critically ill PBT patients in our ICU. Results: Of 59 patients analyzed, ICU mortality was 19% (11/59), and the most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies.

Spiritual well-being and its association with health-related quality of life in primary brain tumor patients.

BACKGROUND: Spirituality can impact patients' attitudes and decisions about treatment and end-of-life care when coping with cancer. Previous studies documented health-related quality of life (HRQoL) and spiritual well-being (SWB) as positively correlated within a general cancer patient population, but little is known about their association in the primary brain tumor population. We sought to measure SWB in primary brain tumor patients and evaluate whether it was associated with HRQoL. METHODS: Six-hundred and six patients treated at The Preston Robert Tisch Brain Tumor Center at Duke between December 16, 2013 and February 28, 2014 with data in the PRoGREss registry are included in this retrospective analysis. Each patient completed the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 (FACIT-Sp-12) and -Fatigue (FACIT-F), and the Functional Assessment of Cancer Therapy-General and -Brain (FACT-G and FACT-Br). RESULTS: Mean age was 49.1 years (SD = 13.5 years), male (N = 328, 54.1%), married (N = 404, 66.7%), at least college-educated (N = 381, 62.9%), and diagnosed with a high-grade glioma (N = 412, 68.0%). Multiple regression analyses were performed on both the FACT-G and the FACT-Br using the FACIT-Sp-12 sub-scales of Meaning/Peace and Faith, FACIT-F, belief in God or a higher power, prayer, gender, tumor grade, and Karnofsky Performance Status (KPS) as predictors. We found that greater SWB (measured by FACIT-Sp-12) was associated with better HRQoL (measured by FACT-G and FACT-Br; p < .0001). CONCLUSION: The association between reported SWB and reported improved HRQoL emphasizes the importance of spirituality in primary brain tumor patients, suggesting SWB must be considered in strategies to improve HRQoL.

Adjuvant Radiation in Older Patients With Glioblastoma: A Retrospective Single Institution Analysis.

OBJECTIVES: Standard 6-week and hypofractionated 3-week courses of adjuvant radiation therapy (RT) are both options for older patients with glioblastoma (GBM), but deciding the optimal regimen can be challenging. This analysis explores clinical factors associated with selection of RT course, completion of RT, and outcomes following RT. MATERIALS AND METHODS: This IRB-approved retrospective analysis identified patients ≥70 years old with GBM who initiated adjuvant RT at our institution between 2004 and 2016. We identified factors associated with standard or hypofractionated RT using the Cochran-Armitage trend test, estimated time-to-event endpoints using the Kaplan-Meier method, and found predictors of overall survival (OS) using Cox proportional hazards models. RESULTS: Sixty-two patients with a median age of 74 (range 70-90) initiated adjuvant RT, with 43 (69%) receiving standard RT and 19 (31%) receiving hypofractionated RT. Selection of short-course RT was associated with older age (p = 0.04) and poor KPS (p = 0.03). Eight (13%) patients did not complete RT, primarily for hospice care due to worsening symptoms. After a median follow-up of 37 months, median OS was 12.3 months (95% CI 9.0-15.1). Increased age (p < 0.05), poor KPS (p < 0.0001), lack of MGMT methylation (p < 0.05), and lack of RT completion (p < 0.0001) were associated with worse OS on multivariate analysis. In this small cohort, GTV size and receipt of standard or hypofractionated RT were not associated with OS. CONCLUSIONS: In this cohort of older patients with GBM, age and KPS was associated with selection of short-course or standard RT. These regimens had similar OS, though a subset of patients experienced worsening symptoms during RT and discontinued treatment. Further investigation into predictors of RT completion and survival may help guide adjuvant therapies and supportive care for older patients.

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Patterns of relapse after successful completion of initial therapy in primary central nervous system lymphoma: a case series.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin's lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed. METHODS: This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival. RESULTS: This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20-86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6). CONCLUSION: After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.

Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide.

PURPOSE: CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. METHODS: One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m2/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1-5 with aprepitant day 1: 125 mg, days 2-5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2-7), as well as safety and quality of life (QoL). RESULTS: Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. CONCLUSIONS: Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV's effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.

The role of chemotherapy in the treatment of central neurocytoma.

Aim: Central neurocytoma (CN) is a rare WHO grade II central nervous system (CNS) tumor. This is an update on chemotherapeutic agents used in its treatment. Patients & methods: An institutional review board-approved, chart review of patients seen at our institution resulted in a single case treated with chemotherapy and is herein included. We proceeded with a comprehensive literature review. Results: We identified 18 citations, representing 39 cases of adult and pediatric CN treated with chemotherapy. With the addition of our single case, the total number of recurrent CN patients treated with temozolomide (TMZ) is nine. Conclusion: There exists marked heterogeneity in chemotherapy used to treat CN. TMZ is incorporated into treatment regimens in the setting of tumor recurrence: its role merits further study.

Second primary cancers in long-term survivors of glioblastoma.

BACKGROUND: Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM. METHODS: Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis. RESULTS: We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1). CONCLUSIONS: Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.

Complementary and integrative health interventions and their association with health-related quality of life in the primary brain tumor population.

BACKGROUND AND PURPOSE: Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life. MATERIALS AND METHODS: Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue. RESULTS: 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation. CONCLUSION: These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.

MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP-null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133+ cells in MTAP-null GBM can be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.