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PURPOSE: Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. Here, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models. EXPERIMENTAL DESIGN: We performed RNA-sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wildtype glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status. RESULTS: Among patient samples, IDH-mutant tumors displayed underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and MDSCs. Introduction of the IDH-mutant enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. CONCLUSIONS: We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant-IDH and may be targetable through therapeutic approaches.
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PURPOSE: Treatment paradigms for isocitrate dehydrogenase (IDH)-mutant gliomas are rapidly evolving. Although typically indolent and responsive to initial treatment, these tumors invariably recur at a higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcomes. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi). EXPERIMENTAL DESIGN: Cell viability, proliferation assays, and flow cytometry were used to examine the pharmacologic effect of two distinct CDKi, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine the efficacy and tolerability of CDKi in vivo. RESULTS: CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in the G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models. CONCLUSIONS: IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support the investigation of the use of these agents in a clinical setting.
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Aminopiridinas , Bencimidazoles , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Glioma , Isocitrato Deshidrogenasa , Mutación , Piperazinas , Inhibidores de Proteínas Quinasas , Piridinas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Glioma/genética , Glioma/tratamiento farmacológico , Glioma/patología , Ratones , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Piridinas/farmacología , Piridinas/uso terapéutico , Línea Celular Tumoral , Eliminación de Gen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , HomocigotoRESUMEN
A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
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Neoplasias Encefálicas , Diferenciación Celular , Isocitrato Deshidrogenasa , Mutación , Oligodendroglioma , Oligodendroglioma/genética , Oligodendroglioma/patología , Oligodendroglioma/tratamiento farmacológico , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Humanos , Diferenciación Celular/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Linaje de la Célula/efectos de los fármacos , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proliferación Celular/efectos de los fármacos , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Ratones , Análisis de la Célula Individual/métodosAsunto(s)
Neoplasias Encefálicas , Glioma , Mutación , Humanos , Glioma/genética , Glioma/patología , Glioma/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Pirimidinas/uso terapéutico , Histonas/genética , Histonas/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
OBJECTIVE: Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment. METHODS: The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions. RESULTS: A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment. CONCLUSIONS: Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Regulación hacia Arriba , Mutación/genética , Glioma/genética , Glioma/patología , Astrocitoma/genética , Microambiente Tumoral/genética , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoAsunto(s)
Neoplasias del Sistema Nervioso Central , Glioma , Humanos , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/terapia , Mutación , Organización Mundial de la SaludRESUMEN
Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.
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Neoplasias Encefálicas , Glioma , Adulto , Humanos , Isocitrato Deshidrogenasa/genética , Consenso , Mutación , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapiaRESUMEN
It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients' tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients' individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients' individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients' individual tumour locations may capture both tumour biology and patients' performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of 'cancer neuroscience'.
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Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/patología , Estudios Transversales , Mutación , Glioma/patología , Encéfalo/patologíaRESUMEN
Standard treatment for patients with IDH-mutant gliomas with radiation therapy and chemotherapy is non-curative and associated with long-term neurotoxicity. This has created intense interest in targeted therapeutic strategies that are specifically designed of IDH-mutant tumors. Much progress has been made in understanding the unique biology of IDH-mutant gliomas, and now various IDH-mutant-specific targeting strategies are in various phases of development. Here, we will review a range of IDH-mutant targeting treatments being explored, including direct IDH inhibitors, as well as strategies that take advantage of IDH-mutant-specific vulnerabilities.
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Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Mutación/genética , Glioma/genética , Glioma/terapia , Glioma/patologíaRESUMEN
Immunotherapy has emerged as a promising approach for treating aggressive solid tumors, even within the CNS. Mutation in the metabolic gene isocitrate dehydrogenase 1 (IDH1) represents not only a major glioma defining biomarker but also an attractive therapeutic neoantigen. As patients with IDH-mutant glioma enter early-phase vaccine and immune checkpoint inhibitor clinical trials, there is emerging evidence that implicates the oncometabolite, 2-hydroxyglutarate (2HG), generated by the neomorphic activity of mutant IDH, as a potential barrier to current immunotherapeutic approaches. Here, the authors review the immunomodulatory and immunosuppressive roles of 2HG within the unique IDH-mutant glioma tumor immune microenvironment and discuss promising immunotherapeutic approaches currently being investigated in preclinical models.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Humanos , Inmunoterapia , Isocitrato Deshidrogenasa/genética , Mutación/genética , Microambiente TumoralRESUMEN
BACKGROUND: For patients with acute, serious neurological conditions presenting to the emergency department (ED), prognostication is typically based on clinical experience, scoring systems and patient co-morbidities. Because estimating a poor prognosis influences caregiver decisions to withdraw life-sustaining therapy, we investigated the consistency of prognostication across a spectrum of neurology physicians. METHODS: Five acute neurological presentations (2 with large hemispheric infarction; 1 with brainstem infarction, 1 with lobar hemorrhage, and 1 with hypoxic-ischemic encephalopathy) were selected for a department-wide prognostication simulation exercise. All had presented to our tertiary care hospital's ED, where a poor outcome was predicted by the ED neurology team within 24 hours of onset. Relevant clinical, laboratory and imaging data available before ED prognostication were presented on a web-based platform to 120 providers blinded to the actual outcome. The provider was requested to rank-order, from most to least likely, the predicted 90-day modified Rankin Scale (mRS) score. To determine the accuracy of individual outcome predictions we compared the patient's the actual 90-day mRS score to highest ranked predicted mRS score. Additionally, the group's "weighted" outcomes, accounting for the entire spectrum of mRS scores ranked by all respondents, were compared to the actual outcome for each case. Consistency was compared between pre-specified provider roles: neurology trainees versus faculty; non-vascular versus vascular faculty. RESULTS: Responses ranged from 106-110 per case. Individual predictions were highly variable, with predictions matching the actual mRS scores in as low as 2% of respondents in one case and 95% in another case. However, as a group, the weighted outcome matched the actual mRS score in 3 of 5 cases (60%). There was no significant difference between subgroups based on expertise (stroke/neurocritical care versus other) or experience (faculty versus trainee) in 4 of 5 cases. CONCLUSION: Acute neuro-prognostication is highly variable and often inaccurate among neurology providers. Significant differences are not attributable to experience or subspecialty expertise. The mean outcome prediction from group of providers ("the wisdom of the crowd") may be superior to that of individual providers.
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Urgencias Médicas , Enfermedades del Sistema Nervioso , Enfermedad Aguda , Servicio de Urgencia en Hospital , Humanos , Enfermedades del Sistema Nervioso/terapia , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. METHODS: The effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. RESULTS: We found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. CONCLUSIONS: Activation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.
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Glioma , Sirtuinas , Citocinas , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , NAD , Sirtuina 1RESUMEN
Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.
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Neoplasias del Sistema Nervioso Central/patología , Hexoquinasa/metabolismo , Linfoma/patología , Factor de Transcripción ReIA/metabolismo , Animales , Antígenos CD79/genética , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/mortalidad , Femenino , Glucólisis , Hexoquinasa/genética , Humanos , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/mortalidad , Ratones SCID , Mutación , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Transducción de Señal , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.