NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Comparison of tumor immune environment between newly diagnosed and recurrent glioblastoma including matched patients.

PURPOSE: Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment, especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined. METHODS: To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients' GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions. RESULTS: We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 and PD-1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs, macrophages, PD-1 or PD-L1+ cells at initial diagnosis did not correlate with OS. TILs, macrophages, and PD-1+ cells were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with a worse prognosis, respectively. CONCLUSIONS: Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Efficacy of sequential radiation and chemotherapy in treating glioblastoma with poor performance status.

INTRODUCTION: While the current standard of care after maximal safe resection for glioblastoma (GBM) is concomitant radiation and chemotherapy, the ideal therapy for patients with poor performance status remains in question due to concerns about treatment tolerance. We sought to evaluate an alternative regimen, sequential radiation and chemotherapy, to assess its efficacy as a treatment option for poorly performing patients. METHODS: We performed a retrospective analysis using the 2015 National Cancer Database in which the survival of patients with a KPS ≤ 70 who received sequential radiation and chemotherapy were compared to those who received radiation therapy alone. Survival outcomes were compared using Kaplan-Meier curves with log rank testing and Cox proportional hazard regression. RESULTS: There were 84 patients analyzed in this study, all of whom had a KPS between 10 and 70. Of those analyzed, 73.8% received radiation therapy alone, and 26.2% received sequential radiation and chemotherapy. There was no difference in survival between the two treatment groups (p = 0.84). Patient age of 70 years or older (n = 31) was associated with decreased survival (HR 1.06 per year, p < 0.0001), regardless of KPS and a KPS of < 70 correlated with a near-significant trend toward worse survival (HR 1.63, p = 0.06). CONCLUSIONS: Treatment with sequential radiation and chemotherapy in poorly performing patients is not associated with an advantage in survival outcome when compared to radiation alone in GBM patients with poor performance status.

Novel therapies hijack the blood-brain barrier to eradicate glioblastoma cancer stem cells.

Glioblastoma (GBM) is amongst the most aggressive brain tumors with a dismal prognosis. Despite significant advances in the current multimodality therapy including surgery, postoperative radiotherapy (RT) and temozolomide (TMZ)-based concomitant and adjuvant chemotherapy (CT), tumor recurrence is nearly universal with poor patient outcomes. These limitations are in part due to poor drug penetration through the blood-brain barrier (BBB) and resistance to CT and RT by a small population of cancer cells recognized as tumor-initiating cells or cancer stem cells (CSCs). Though CT and RT kill the bulk of the tumor cells, they fail to affect CSCs, resulting in their enrichment and their development into more refractory tumors. Therefore, identifying the mechanisms of resistance and developing therapies that specifically target CSCs can improve response, prevent the development of refractory tumors and increase overall survival of GBM patients. Small molecule inhibitors that can breach the BBB and selectively target CSCs are emerging. In this review, we have summarized the recent advancements in understanding the GBM CSC-specific signaling pathways, the CSC-tumor microenvironment niche that contributes to CT and RT resistance and the use of novel combination therapies of small molecule inhibitors that may be used in conjunction with TMZ-based chemoradiation for effective management of GBM.

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201.

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

Targeting the Sanctuary Site: Options when Breast Cancer Metastasizes to the Brain.

Brain metastasis is a poor prognostic factor in breast cancer progression, and traditional treatment options have shown minimal response with overall low median survival rates. The incidence of brain metastasis has been increasing despite and, in part, due to advancements in treatment as a result of prolongation of survival. Targeted therapy such anti-HER2 agents have a lower efficacy in this setting compared to metastases elsewhere; however, novel therapies are emerging in this regard. In this comprehensive review, we discuss risk per subtype, special considerations for therapy selection, current focal and systemic treatments, and recent advancements and potential future targets for success. We present our treatment paradigm and multidisciplinary approach to brain metastases arising from breast cancer based on the available evidence, incorporating molecular characteristics.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Targeted Treatment of Brain Metastases.

PURPOSE OF REVIEW: Brain metastases are the most common intracranial tumors in adults. Historically, the median survival after the diagnosis of brain metastases has been dismal and medical therapies had a limited role in the management of these patients. RECENT FINDINGS: The advent of targeted therapy has ushered in an era of increased hope for patients with brain metastases. The most common malignancies that result in brain metastases-melanoma, lung cancer, and breast cancer, often have actionable mutations, which make them good candidates for targeted systemic therapy. These brain metastases have been shown to have relevant and sometimes divergent genetic alterations, and there has been a resurgence of interest in targeted drug delivery to the brain by using standard or pulsatile dosing to achieve adequate concentration in the brain. An increased understanding of oncogenic alterations, a surge in targeted drug development with good blood barrier penetration, and inclusion of patients with active brain metastases on clinical trials have led to improved outcomes for patients with brain metastases.

Operational Failures Detected by Frontline Acute Care Nurses.

Frontline nurses encounter operational failures (OFs), or breakdowns in system processes, that hinder care, erode quality, and threaten patient safety. Previous research has relied on external observers to identify OFs; nurses have been passive participants in the identification of system failures that impede their ability to deliver safe and effective care. To better understand frontline nurses' direct experiences with OFs in hospitals, we conducted a multi-site study within a national research network to describe the rate and categories of OFs detected by nurses as they provided direct patient care. Data were collected by 774 nurses working in 67 adult and pediatric medical-surgical units in 23 hospitals. Nurses systematically recorded data about OFs encountered during 10 work shifts over a 20-day period. In total, nurses reported 27,298 OFs over 4,497 shifts, a rate of 6.07 OFs per shift. The highest rate of failures occurred in the category of Equipment/Supplies, and the lowest rate occurred in the category of Physical Unit/Layout. No differences in OF rate were detected based on hospital size, teaching status, or unit type. Given the scale of this study, we conclude that OFs are frequent and varied across system processes, and that organizations may readily obtain crucial information about OFs from frontline nurses. Nurses' detection of OFs could provide organizations with rich, real-time information about system operations to improve organizational reliability. © 2017 Wiley Periodicals, Inc.

Central Nervous System Cancers, Version 1.2015.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.

Exploratory analysis of the spatial distribution of adult glioma age-adjusted county incidence rates, Nebraska Medicine, 2009-2019.

Background: Central nervous system (CNS) cancers including gliomas have low incidence but high mortality. The age-adjusted incidence rate for CNS cancers is higher in Nebraska than nationally. This exploratory study was motivated by glioma patient inquiries about possible clustering of cases within the state to see if more in-depth investigation was warranted. Methods: Using electronic health records from Nebraska Medicine, we identified Nebraska adult (age ≥19) glioma patients diagnosed between January 1, 2009 and November 1, 2019. Patient residential addresses were geocoded, mapped, and combined with annual US Census data to compute age-adjusted incidence rates (AAIR) at the county level. Counties with fewer than five cases were excluded to protect patient identity. ArcGIS software was used for geocoding and mapping. Results: Of the 285 cases included in the analysis, 53.2% were geocoded with exact match and the remainder were processed manually. Cases occurred in 47 of the 93 counties. After data suppression, 11 counties (228 cases) visually clustered in eastern and central Nebraska with AAIR ranging from 0.85 to 5.66 per 100 000. Conclusions: Many counties in the state were excluded from analysis of this rare cancer due to the small number of cases leading to unstable rates and the need to suppress data to protect patient privacy. However, this preliminary study suggests that glioma incidence is highest in central and eastern Nebraska. Next steps include analysis of state cancer registry data to ensure more complete case ascertainment.

Biological, diagnostic and therapeutic implications of exosomes in glioma.

Despite therapeutic advances, overall survival in glioblastoma is dismal. To optimize progress, a more detailed understanding of glioma's molecular, cellular, and intercellular pathophysiology is needed. Recent investigation has revealed a vital role for exosomes in inter-cellular signaling, tumor cell support, and regulation of the tumor microenvironment. Exosomes carry miRNAs, lncRNAs, mRNAs, proteins, immune regulatory molecules, nucleic acids, and lipids; however, the composition of exosome cargo is variable depending on the cell of origin. Specific exosomal miRNA contents such as miR-21, miR-301a, miR-151a, miR-148a, and miR-5096 are altered in high-grade glioma. Unique proteomic, genomic, and miRNA signatures of tumor exosomes have been associated with disease pathobiology, temozolomide resistance, immunosuppression, and tumor proliferation. Exosomes hold promise for tissue diagnostic glioma diagnosis and monitoring response to therapy. This review summarizes the current understanding of exosomes, their crucial role in glioma pathology, and future directions for their use in diagnosis and treatment. METHODS: The MEDLINE/PubMed database was reviewed for papers written in English and publication dates of 1981-2023, using the search string "Exosome", "Extracellular vesicles", "Glioma", "Exosomes in glioma".

Pathophysiological role of histamine signaling and its implications in glioblastoma.

Glioblastoma (GBM), an extremely aggressive and prevalent malignant brain tumor, remains a challenge to treat. Despite a multimodality treatment approach, GBM recurrence remains inevitable, particularly with the emergence of temozolomide (TMZ) resistance and limited treatment options. Surprisingly, previous studies show that a history of allergies, atopy, or asthma is inversely associated with GBM risk. Further, the electronic medical record at the University Hospital of Lausanne showed that the GBM patients taking antihistamine during treatment had better survival. Histamine is an essential neurotransmitter in the brain and plays a significant role in regulating sleep, hormonal balance, and cognitive functions. Elevated levels of histamine and increased histamine receptor expression have been found in different tumors and their microenvironments, including GBM. High histamine 1 receptor (HRH1) expression is inversely related to overall and progression-free survival in GBM patients, further emphasizing the role of histamine in disease progression. This review aims to provide insights into the challenges of GBM treatment, the role of histamine in GBM progression, and the rationale for considering antihistamines as targeted therapy. The review concludes by encouraging further investigation into antihistamine mechanisms and their impact on the tumor microenvironment.

Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies.

Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Outcomes for patients with anaplastic astrocytoma treated with chemoradiation, radiation therapy alone or radiation therapy followed by chemotherapy: a retrospective review within the era of temozolomide.

Treatment for anaplastic astrocytoma (AA) is controversial. To assess three primary treatment approaches, patients from a single institution were retrospectively evaluated. To represent modern treatment selection, patients diagnosed with AA from December 2003 to December 2009 were selected. Those with insufficient data, incomplete pathology, and transformation or reclassification to glioblastoma in fewer than 6 months were excluded. A total of 163 patients were included in the final analyses. Median follow-up time was 4.2 years (range 0.5-7.8 years). Median age and Karnofsky performance status at diagnosis were 39.2 years and 90, respectively. 23.6 % of patients underwent biopsy, and 72.2 % underwent resection. Approximately 31 % received concurrent chemoradiation (CRT), 26.1 % had radiation therapy alone (RT), 38.2 % had radiation therapy followed by chemotherapy (RT-C), and 3 % were treated only with chemotherapy. Temozolomide was used almost exclusively during CRT (94.2 %) and adjuvantly. A median of 9.5 cycles of adjuvant chemotherapy was given. The combination of radiation and chemotherapy, either concurrent or sequential trended toward a higher rate of radiation necrosis. Median progression free survival (PFS) favored RT (not reached) over CRT (1.5 years) and RT-C (3.6 years) adjusted for pairwise comparison (p = 0.033, p = 0.050). Median overall survival (OS) was 5.7 years, and did not differ significantly by treatment group. OS for patients with AA did not vary by initial treatment selection. Although the longer PFS in those receiving RT versus CRT may be confounded by pseudoprogression, the equivalent OS among groups supports RT.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.