Lysine catabolism reprograms tumour immunity through histone crotonylation.

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3-5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8+ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.

The role of spine stereotactic radiosurgery for patients with breast cancer metastases.

PURPOSE: Breast cancer that metastasizes to the spine is associated with low quality of life and poor survival. Radiosurgery has an increasing role in this patient population. This single-institution (2003-2023) study analyzes clinical outcomes and prognostic factors for patients who underwent spinal stereotactic radiosurgery (SSRS) for metastatic breast cancer. METHODS: Ninety patients (155 unique breast cancer spinal metastases) were treated with SSRS. The median age was 57 years (range: 35-88), and the median KPS was 80 (range: 40-100). Forty-two (27%) lesions were managed surgically prior to radiosurgery. At SSRS, 75 (48%) lesions impinged or compressed the spinal cord per the epidural spinal cord scale (ESCC). Seventy-nine (51%) lesions were categorized as potentially unstable or unstable by the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 15 months (range: 1-183). The median single-session tumor volume was 25.4 cc (range: 2-197), and the median single-fraction prescription dose was 17 Gy (range: 12-25). Seven (5%) lesions locally progressed. The 1-, 2-, and 5-year local control rates were 98%, 97%, and 92%, respectively. The median overall survival (OS) for the cohort was 32 months (range: 2-183). The 1-, 2-, and 5-year OS rates were 72%, 53%, and 30%, respectively. On univariate analysis, KPS ≥ 80 (p = 0.009, HR: 0.51, 95% CI: 0.31-0.84) was associated with improved OS. Patient-reported pain improved (68%), remained stable (29%), or worsened (3%) following radiosurgery. Fifteen (10%) radiation-induced toxicities were reported. CONCLUSIONS: Spinal radiosurgery is a safe and highly effective long-term treatment modality for metastases to the spine that originate from breast cancer.

Fluorescence-guided resection of intradural spinal tumors: a systematic review and meta-analysis.

Intradural spinal tumors present significant challenges due to involvement of critical motor and sensory tracts. Achieving maximal resection while preserving functional tissue is therefore crucial. Fluorescence-guided surgery aims to improve resection accuracy and is well studied for brain tumors, but its efficacy has not been fully assessed for spinal tumors. This meta-analysis aims to delineate the efficacy of fluorescence guidance in intradural spinal tumor resection. The authors performed a systematic review in four databases. We included studies that have utilized fluorescence agents, 5-aminolevulinic acid (5-ALA) or sodium fluorescein, for the resection of intradural spinal tumors. A meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 12 studies involving 552 patients undergoing fluorescence-guided intradural spinal tumor resection were included. Meningiomas demonstrated a 98% fluorescence rate and were associated with a homogenous florescence pattern; however, astrocytomas had variable fluorescence rate with pooled proportion of 70%. There was no significant difference in gross total resection (GTR) rates between fluorescein and 5-ALA (94% vs 84%, p = .22). Pre-operative contrast enhancement was significantly associated with intraoperative fluorescence with fluorescein. Intramedullary tumors with positive intraoperative fluorescence were significantly associated with higher GTR rates (96% vs 73%, p = .03). Utilizing fluorescence guidance during intradural spinal tumor resection holds promise of improving intraoperative visualization for specific intradural spinal tumors. Meningiomas and ependymomas have the highest fluorescence rates especially with sodium fluorescein; on the other hand, astrocytomas have variable fluorescence rates with no superiority of either agent. Positive fluorescence of intramedullary tumors is associated with a higher degree of resection.

Comparative metabolomics in the Pahenu2 classical PKU mouse identifies cerebral energy pathway disruption and oxidative stress.

Classical phenylketonuria (PKU, OMIM 261600) owes to hepatic deficiency of phenylalanine hydroxylase (PAH) that enzymatically converts phenylalanine (Phe) to tyrosine (Tyr). PKU neurologic phenotypes include impaired brain development, decreased myelination, early onset mental retardation, seizures, and late-onset features (neuropsychiatric, Parkinsonism). Phe over-representation is systemic; however, tissue response to hyperphenylalaninemia is not consistent. To characterize hyperphenylalaninemia tissue response, metabolomics was applied to Pahenu2 classical PKU mouse blood, liver, and brain. In blood and liver over-represented analytes were principally Phe, Phe catabolites, and Phe-related analytes (Phe-conjugates, Phe-containing dipeptides). In addition to Phe and Phe-related analytes, the metabolomic profile of Pahenu2 brain tissue evidenced oxidative stress responses and energy dysregulation. Glutathione and homocarnosine anti-oxidative responses are apparent Pahenu2 brain. Oxidative stress in Pahenu2 brain was further evidenced by increased reactive oxygen species. Pahenu2 brain presents an increased NADH/NAD ratio suggesting respiratory chain complex 1 dysfunction. Respirometry in Pahenu2 brain mitochondria functionally confirmed reduced respiratory chain activity with an attenuated response to pyruvate substrate. Glycolysis pathway analytes are over-represented in Pahenu2 brain tissue. PKU pathologies owe to liver metabolic deficiency; yet, Pahenu2 liver tissue shows neither energy disruption nor anti-oxidative response. Unique aspects of metabolomic homeostasis in PKU brain tissue along with increased reactive oxygen species and respiratory chain deficit provide insight to neurologic disease mechanisms. While some elements of assumed, long standing PKU neuropathology are enforced by metabolomic data (e.g. reduced tryptophan and serotonin representation), energy dysregulation and tissue oxidative stress expand mechanisms underlying neuropathology.

Phenylalanine hydroxylase deficient phenylketonuria comparative metabolomics identifies energy pathway disruption and oxidative stress.

Classical phenylketonuria (PKU, OMIM 261600) owes to hepatic deficiency of phenylalanine hydroxylase (PAH) that enzymatically converts phenylalanine (Phe) to tyrosine (Tyr). PKU neurologic phenotypes include impaired brain development, decreased myelination, early onset mental retardation, seizures, and late-onset features (neuropsychiatric, Parkinsonism). PAH deficiency leads to systemic hyperphenylalaninemia; however, the impact of Phe varies between tissues. To characterize tissue response to hyperphenylalaninemia, metabolomics was applied to tissue from therapy noncompliant classical PKU patients (blood, liver), the Pahenu2 classical PKU mouse (blood, liver, brain) and the PAH deficient pig (blood, liver, brain, cerebrospinal fluid). In blood, liver, and CSF from both patients and animal models over-represented analytes were principally Phe, Phe catabolites, and Phe-related analytes (conjugates, Phe-containing dipeptides). In addition to Phe and Phe-related analytes, the metabolomic profile of PKU brain tissue (mouse, pig) evidenced oxidative stress responses and energy dysregulation. In Pahenu2 and PKU pig brain tissues, anti-oxidative response by glutathione and homocarnosine is apparent. Oxidative stress in Pahenu2 brain was further demonstrated by increased reactive oxygen species. In Pahenu2 and PKU pig brain, an increased NADH/NAD ratio suggests a respiratory chain dysfunction. Respirometry in PKU brain mitochondria (mouse, pig) functionally confirmed reduced respiratory chain activity. Glycolysis pathway analytes are over-represented in PKU brain tissue (mouse, pig). PKU pathologies owe to liver metabolic deficiency; yet, PKU liver tissue (mouse, pig, human) shows neither energy disruption nor anti-oxidative response. Unique aspects of metabolomic homeostasis in PKU brain tissue along with increased reactive oxygen species and respiratory chain deficit provide insight to neurologic disease mechanisms. While some elements of assumed, long standing PKU neuropathology are enforced by metabolomic data (e.g. reduced tryptophan and serotonin representation), energy dysregulation and tissue oxidative stress expand mechanisms underlying neuropathology.

A contemporary update on glioblastoma: molecular biology, current management, and a vision towards bio-adaptable personalized care.

INTRODUCTION: Glioblastoma (GBM) is the most fatal brain tumor in adults. Current survival rates of GBM remain below 2 years due to GBM's aggressive cellular migration and genetically driven treatment escape pathways. Despite our rapidly increasing understanding of GBM biology, earlier diagnoses, and refined surgical techniques, only moderate survival benefits have been achieved. Nonetheless, the pressing need for better survival rates has brought forward a multitude of newer therapeutic approaches and opened the door for potential personalization of these modalities in the near future. METHODS: We reviewed the published literature discussing the current state of knowledge regarding GBM biology and therapy and summarized the information that may point toward future personalized therapeutic strategies. RESULTS: Several novel modalities such as oncolytic viruses, targeted immune, and molecular therapies, and tumor treating fields have been introduced. To date, there is no single treatment modality for GBM, but rather a wide spectrum of combined modalities that address intratumoral cellular and genetic variabilities. While the current state of GBM research and clinical trial landscape may hold promise, current literature lacks any fruitful progress towards personalized GBM therapy. CONCLUSION: In this review, we are discussing our recent knowledge of the GBM genetic biologic landscape and the current advances in therapy, as well as providing a blueprint for an envisioned GBM management paradigm that should be personalized and adaptable to accommodate each patient's diverse genetic variations and therapy response/escape patterns.

History of atopy confers improved outcomes in IDH mutant and wildtype lower grade gliomas.

PURPOSE: A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. METHODS: Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. RESULTS: 374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5 months, p = 00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85 months, p = 0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p = 0.002, HR 0.257, 95% 0.109-0.604), (p = < 0.001, HR 0.217, 95% 0.107-0.444), and (p = 0.004, HR 2.72, 95% 1.373-5.397), respectively. In terms of treatment outcomes, patients with atopy did not differ in treatment response compared to their counterpart. Pathway analysis demonstrated an upstream activation of the BDNF pathway (p = 0.00027). CONCLUSION: A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.

Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome.

INTRODUCTION: The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients. METHODS: We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups. RESULTS: Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected = 0.002; older age: HR 1.034, p-corrected = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV ≥ 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037). CONCLUSION: Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma.

Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.

Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact.

Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes. SIGNIFICANCE STATEMENT: Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not mechanism based and its prognostic value is limited. Here, we identify a new mechanism in GBM (the miR-21-Sox2 axis) that can classify ∼50% of patients into two subtypes with distinct molecular, radiological, and pathological characteristics. Importantly, this classification can predict patient survival better than the currently used parameters. Further, analysis of the miR-21-Sox2 relationship in mouse neural stem cells and in the mouse brain at different developmental stages indicates that miR-21 and Sox2 are predominantly expressed in mutually exclusive patterns, suggesting a role in normal neural development.

Glioblastoma: imaging genomic mapping reveals sex-specific oncogenic associations of cell death.

PURPOSE: To identify the molecular profiles of cell death as defined by necrosis volumes at magnetic resonance (MR) imaging and uncover sex-specific molecular signatures potentially driving oncogenesis and cell death in glioblastoma (GBM). MATERIALS AND METHODS: This retrospective study was HIPAA compliant and had institutional review board approval, with waiver of the need to obtain informed consent. The molecular profiles for 99 patients (30 female patients, 69 male patients) were identified from the Cancer Genome Atlas, and quantitative MR imaging data were obtained from the Cancer Imaging Archive. Volumes of necrosis at MR imaging were extracted. Differential gene expression profiles were obtained in those patients (including male and female patients separately) with high versus low MR imaging volumes of tumor necrosis. Ingenuity Pathway Analysis was used for messenger RNA-microRNA interaction analysis. A histopathologic data set (n = 368; 144 female patients, 224 male patients) was used to validate the MR imaging findings by assessing the amount of cell death. A connectivity map was used to identify therapeutic agents potentially targeting sex-specific cell death in GBM. RESULTS: Female patients showed significantly lower volumes of necrosis at MR imaging than male patients (6821 vs 11 050 mm(3), P = .03). Female patients, unlike male patients, with high volumes of necrosis at imaging had significantly shorter survival (6.5 vs 14.5 months, P = .01). Transcription factor analysis suggested that cell death in female patients with GBM is associated with MYC, while that in male patients is associated with TP53 activity. Additionally, a group of therapeutic agents that can potentially be tested to target cell death in a sex-specific manner was identified. CONCLUSION: The results of this study suggest that cell death in GBM may be driven by sex-specific molecular pathways.

Addition of MR imaging features and genetic biomarkers strengthens glioblastoma survival prediction in TCGA patients.

PURPOSE: The purpose of our study was to assess whether a model combining clinical factors, MR imaging features, and genomics would better predict overall survival of patients with glioblastoma (GBM) than either individual data type. METHODS: The study was conducted leveraging The Cancer Genome Atlas (TCGA) effort supported by the National Institutes of Health. Six neuroradiologists reviewed MRI images from The Cancer Imaging Archive (http://cancerimagingarchive.net) of 102 GBM patients using the VASARI scoring system. The patients' clinical and genetic data were obtained from the TCGA website (http://www.cancergenome.nih.gov/). Patient outcome was measured in terms of overall survival time. The association between different categories of biomarkers and survival was evaluated using Cox analysis. RESULTS: The features that were significantly associated with survival were: (1) clinical factors: chemotherapy; (2) imaging: proportion of tumor contrast enhancement on MRI; and (3) genomics: HRAS copy number variation. The combination of these three biomarkers resulted in an incremental increase in the strength of prediction of survival, with the model that included clinical, imaging, and genetic variables having the highest predictive accuracy (area under the curve 0.679±0.068, Akaike's information criterion 566.7, P<0.001). CONCLUSION: A combination of clinical factors, imaging features, and HRAS copy number variation best predicts survival of patients with GBM.

Preoperative stereotactic radiosurgery for cerebral metastases: safe, effective, and decreases steroid dependency.

OBJECTIVE: Preoperative stereotactic radiosurgery (SRS) is emerging as a viable alternative to standard postoperative SRS. Studies have suggested that preoperative SRS provides comparable tumor control and overall survival (OS) and may reduce the incidence of leptomeningeal disease (LMD) and adverse radiation effects (AREs). It is unknown, however, if preoperative SRS remains effective in cohorts including large brain metastases (> 14 cm3) or if preoperative SRS affects steroid taper/immunotherapy. Here, the authors report the results of a phase 2 single-arm trial assessing a prospectively acquired series of 26 patients who underwent preoperative SRS, without a volumetric cutoff, compared with a propensity score-matched concurrent cohort of 30 patients who underwent postoperative SRS to address these salient questions. METHODS: Demographics, oncological history, surgical details, and outcomes were collected from the medical records. Coprimary endpoints were local tumor control (LTC) and a composite outcome of LTC, ARE, and LMD. Additional outcomes were OS, steroid taper details, and immunotherapy resumption. For survival analyses, cohorts were propensity score matched. RESULTS: Preoperative and postoperative SRS patients were comparable in terms of age, sex, Karnofsky Performance Status score, oncological history, and operative details. Gross tumor volume (GTV) was significantly higher in the preoperative group (median 12.2 vs 5.3 cm3, p < 0.001). One-year LTC (preoperative SRS: 77.2% vs postoperative SRS: 82.5%, p = 0.61) and composite outcome (68.3% vs 72.7%, p = 0.38) were not significantly different between the groups. In multivariable analysis, preoperative SRS did not have a significant effect on LTC (HR 1.57 [95% CI 0.38-6.49], p = 0.536) or the composite outcome (HR 1.18 [95% CI 0.38-3.72], p = 0.771), although the confidence intervals were large. The median OS (preoperative SRS: 17.0 vs postoperative SRS: 14.0 months, p = 0.61) was not significantly different. Rates of LMD were nonsignificantly lower in the preoperative SRS group (3.8% vs 16.7%, p = 0.200). Greater GTV volume was associated with prolonged (> 10 days) steroid taper (OR 1.24 [95% CI 1.04-1.55], p = 0.032). However, in multivariable analysis, preoperative SRS markedly reduced the steroid taper length (OR 0.13 [95% CI 0.02-0.61], p = 0.016). Time to immunotherapy was shorter in the preoperative SRS group (36 [IQR 26, 76] vs OR 228 [IQR 129, 436] days, p = 0.02). CONCLUSIONS: Compared with postoperative SRS, preoperative SRS is a safe and effective strategy in the management of cerebral metastases of all sizes and provides comparable tumor control without increased adverse effects. Notably, preoperative SRS enabled rapid steroid taper, even in larger tumors. Future studies should specifically examine the interaction of preoperative SRS with steroid usage and resumption of systemic therapies and the subsequent effects on systemic progression and OS.

Associating T1-Weighted and T2-Weighted Magnetic Resonance Imaging Radiomic Signatures With Preoperative Symptom Severity in Patients With Cervical Spondylotic Myelopathy.

BACKGROUND: Preoperative symptom severity in cervical spondylotic myelopathy (CSM) can be variable. Radiomic signatures could provide an imaging biomarker for symptom severity in CSM. This study utilizes radiomic signatures of T1-weighted and T2-weighted magnetic resonance imaging images to correlate with preoperative symptom severity based on modified Japanese Orthopaedic Association (mJOA) scores for patients with CSM. METHODS: Sixty-two patients with CSM were identified. Preoperative T1-weighted and T2-weighted magnetic resonance imaging images for each patient were segmented from C2-C7. A total of 205 texture features were extracted from each volume of interest. After feature normalization, each second-order feature was further subdivided to yield a total of 400 features from each volume of interest for analysis. Supervised machine learning was used to build radiomic models. RESULTS: The patient cohort had a median mJOA preoperative score of 13; of which, 30 patients had a score of >13 (low severity) and 32 patients had a score of ≤13 (high severity). Radiomic analysis of T2-weighted imaging resulted in 4 radiomic signatures that correlated with preoperative mJOA with a sensitivity, specificity, and accuracy of 78%, 89%, and 83%, respectively (P < 0.004). The area under the curve value for the ROC curves were 0.69, 0.70, and 0.77 for models generated by independent T1 texture features, T1 and T2 texture features in combination, and independent T2 texture features, respectively. CONCLUSIONS: Radiomic models correlate with preoperative mJOA scores using T2 texture features in patients with CSM. This may serve as a surrogate, objective imaging biomarker to measure the preoperative functional status of patients.

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

MR imaging predictors of molecular profile and survival: multi-institutional study of the TCGA glioblastoma data set.

PURPOSE: To conduct a comprehensive analysis of radiologist-made assessments of glioblastoma (GBM) tumor size and composition by using a community-developed controlled terminology of magnetic resonance (MR) imaging visual features as they relate to genetic alterations, gene expression class, and patient survival. MATERIALS AND METHODS: Because all study patients had been previously deidentified by the Cancer Genome Atlas (TCGA), a publicly available data set that contains no linkage to patient identifiers and that is HIPAA compliant, no institutional review board approval was required. Presurgical MR images of 75 patients with GBM with genetic data in the TCGA portal were rated by three neuroradiologists for size, location, and tumor morphology by using a standardized feature set. Interrater agreements were analyzed by using the Krippendorff α statistic and intraclass correlation coefficient. Associations between survival, tumor size, and morphology were determined by using multivariate Cox regression models; associations between imaging features and genomics were studied by using the Fisher exact test. RESULTS: Interrater analysis showed significant agreement in terms of contrast material enhancement, nonenhancement, necrosis, edema, and size variables. Contrast-enhanced tumor volume and longest axis length of tumor were strongly associated with poor survival (respectively, hazard ratio: 8.84, P = .0253, and hazard ratio: 1.02, P = .00973), even after adjusting for Karnofsky performance score (P = .0208). Proneural class GBM had significantly lower levels of contrast enhancement (P = .02) than other subtypes, while mesenchymal GBM showed lower levels of nonenhanced tumor (P < .01). CONCLUSION: This analysis demonstrates a method for consistent image feature annotation capable of reproducibly characterizing brain tumors; this study shows that radiologists' estimations of macroscopic imaging features can be combined with genetic alterations and gene expression subtypes to provide deeper insight to the underlying biologic properties of GBM subsets.