RESUMEN
BACKGROUND: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).
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Neoplasias del Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Viroterapia Oncolítica , Virus Oncolíticos , Adenoviridae , Adolescente , Astrocitoma/radioterapia , Astrocitoma/terapia , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/patología , Neoplasias del Tronco Encefálico/radioterapia , Neoplasias del Tronco Encefálico/terapia , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/mortalidad , Glioma Pontino Intrínseco Difuso/radioterapia , Glioma Pontino Intrínseco Difuso/terapia , Glioma/radioterapia , Glioma/terapia , Humanos , Infusiones Intralesiones , Viroterapia Oncolítica/efectos adversos , Viroterapia Oncolítica/métodos , Calidad de Vida , Microambiente TumoralRESUMEN
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating diseases among children with cancer, thus novel strategies are urgently needed. AIMS: We retrospectively evaluated DIPG patients exposed to the carbohydrate restricted ketogenic diet (KD) with regard of feasibility, safety, and overall survival (OS). METHODS AND RESULTS: Searches of MEDLINE and Embase identified five hits meeting the search criteria (diagnosis of DIPG and exposure to KD). One additional case was identified by contact with experts. Individual patient data were extracted from publications or obtained from investigators. The inclusion criteria for analysis of the data were defined as DIPG patients who were exposed to the KD for ≥3 months. Feasibility, as described in the literature, was the number of patients able to follow the KD for 3 months out of all DIPG patients identified. OS was estimated by the Kaplan-Meier method. Five DIPG patients (males, n = 3; median age 4.4 years; range, 2.5-15 years) meeting the inclusion criteria were identified. Analysis of the available data suggested that the KD is generally relatively well tolerated. Only mild gastro-intestinal complaints, one borderline hypoglycemia (2.4 mmol/L) and one hyperketosis (max 7.2 mmol/L) were observed. Five out of six DIPG patients identified adhered for ≥3 months (median KD duration, 6.5 months; range, 0.25-2 years) to the diet. The median OS was 18.7 months. CONCLUSION: Our study provides evidence that it may be feasible for pediatric DIPG patients to adhere for at least 3 months to KD. In particular cases, diet modifications were done. The clinical outcome and OS appear not to be impacted in a negative way. KD might be proposed as adjuvant therapy when large prospective studies have shown feasibility and safety. Future studies might ideally assess the impact of KD on clinical outcome, quality of life, and efficacy.
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Neoplasias del Tronco Encefálico/mortalidad , Dieta Cetogénica/métodos , Glioma Pontino Intrínseco Difuso/mortalidad , Calidad de Vida , Adolescente , Neoplasias del Tronco Encefálico/dietoterapia , Neoplasias del Tronco Encefálico/patología , Niño , Preescolar , Dieta Cetogénica/mortalidad , Glioma Pontino Intrínseco Difuso/dietoterapia , Glioma Pontino Intrínseco Difuso/patología , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
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Antineoplásicos/farmacología , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Proteínas de Unión al ADN/genética , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Epigénesis Genética , Proteínas del Grupo de Alta Movilidad/genética , Histonas/genética , Neuroglía/efectos de los fármacos , Factores de Elongación Transcripcional/genética , Acetilación , Animales , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/patología , Carbazoles/farmacología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Niño , Cromatina/química , Cromatina/metabolismo , Proteínas de Unión al ADN/metabolismo , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidad , Glioma Pontino Intrínseco Difuso/patología , Sinergismo Farmacológico , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Epigenoma , Proteínas del Grupo de Alta Movilidad/metabolismo , Histonas/antagonistas & inhibidores , Histonas/metabolismo , Humanos , Metilación , Ratones , Neuroglía/metabolismo , Neuroglía/patología , Panobinostat/farmacología , Cultivo Primario de Células , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Transducción de Señal , Análisis de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Elongación Transcripcional/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: We present our institutional approach for re-irradiation in diffuse intrinsic pontine glioma and their outcomes. METHODS: Consecutive patients of recurrent diffuse intrinsic pontine glioma treated with re-irradiation (January 2015-September 2019) were reviewed retrospectively to describe the clinical-response-based approach followed for the dose and volume decision. Outcomes were defined with clinical and steroid response criteria and survival endpoints included progression-free survival and overall survival as cumulative(c) overall survival and re-irradiation overall survival (re-irradiation starting to death). The Kaplan-Meier method and log-rank test were used for survival analysis. RESULTS: Twenty-patient cohort with a median (m) age of 7.5 years, m-progression-free survival of 8.4 months and m-Lansky performance score of 50 received re-irradiation of which 17 (85%) were called clinical responders. The median re-irradiation-overall survival with 39.6-41.4, 43.2 and 45 Gy were 5.8, 7 and 5.3 months, respectively. One-month post-re-irradiation steroid independent status was a significant predictor of better survival outcomes (overall survival, P≤0.004). No ≥ grade 3 toxicities were noticed. Two patients succumbed to intra-tumoral hemorrhage. CONCLUSIONS: Higher doses of re-irradiation based on a clinical-response-based approach show improvement in survival and steroid dependence rates with acceptable toxicity. Steroid independent status at 1-month post-re-irradiation predicts better outcomes. Prospective studies may validate this with quality of life data.
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Neoplasias del Tronco Encefálico/radioterapia , Glioma Pontino Intrínseco Difuso/radioterapia , Calidad de Vida/psicología , Reirradiación/métodos , Neoplasias del Tronco Encefálico/mortalidad , Niño , Estudios de Cohortes , Glioma Pontino Intrínseco Difuso/mortalidad , Femenino , Humanos , Masculino , Supervivencia sin Progresión , Estudios Prospectivos , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are the most fatal primary brainstem tumors in pediatric patients. The identification of new molecular features, mediating their formation and progression, as non-coding RNAs (ncRNAs), would be of great importance for the development of effective treatments. METHODS: We analyzed the DIPGs transcriptome with the HTA2.0 array and it was compared with pediatric non-brainstem astrocytoma expression profiles (GSE72269). RESULTS: More than 50% of the differentially expressed transcripts were ncRNAs and based on this, we proposed a DIPGs ncRNA signature. LncRNAs XIST and XIST-210, and the HBII-52 and HBII-85 snoRNA clusters were markedly downregulated in DIPGs. qPCR assays demonstrated XIST downregulation in all non-brainstem astrocytomas, in a gender, age, and brain location-independent manner, as well as in DIPGs affecting boys; however, DIPGs affecting girls showed both downregulation and upregulation of XIST. Girls' with longer survival positively correlated with XIST expression. CONCLUSIONS: The involvement of ncRNAs in DIPGs is imminent and their expression profile is useful to differentiate them from non-neoplastic tissues and non-brain stem astrocytomas, which suggests their potential use as DIPG biomarkers. In fact, XIST and XIST-210 are potential DIPG prognostic biomarkers.
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Biomarcadores de Tumor/metabolismo , Neoplasias del Tronco Encefálico/diagnóstico , Glioma Pontino Intrínseco Difuso/diagnóstico , ARN no Traducido/metabolismo , Transcriptoma , Adolescente , Factores de Edad , Empalme Alternativo , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/mortalidad , Niño , Preescolar , Bases de Datos Genéticas , Glioma Pontino Intrínseco Difuso/diagnóstico por imagen , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidad , Regulación hacia Abajo , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , ARN Nucleolar Pequeño/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores Sexuales , Regulación hacia ArribaRESUMEN
To evaluate the contribution of 18F-dihydroxyphenylalanine (DOPA) PET in association with conventional MRI in predicting treatment response and survival outcome of pediatric patients with diffuse intrinsic pontine gliomas (DIPGs). Methods: We retrospectively analyzed 19 children with newly diagnosed DIPGs who underwent 18F-DOPA PET/CT and conventional MRI within one week of each other at admission and subsequent MRI follow-up. Following co-registration and fusion of PET and MRI, 18F-DOPA uptake avidity and extent (PET tumor volume and uniformity) at admission, along with MRI indices including presence of ring contrast-enhancement, tumor volume at admission and at maximum response following first-line treatment, were evaluated and correlated with overall survival (OS). The association between 18F-DOPA uptake tumor volume at admission and MRI tumor volume following treatment was evaluated. Statistics included Wilcoxon signed-rank and Mann-Whitney U tests, Kaplan-Meier OS curve and Cox analysis. Results: DIPGs with a 18F-DOPA uptake Tumor/Striatum (T/S) ratio >1 presented an OS ≤ 12 months and lower degree of tumor volume reduction following treatment (p = 0.001). On multivariate analysis, T/S (p = 0.001), ring enhancement (p = 0.01) and the degree of MRI tumor volume reduction (p = 0.01) independently correlated with OS. In all patients, areas of increased 18F-DOPA uptake overlapped with regions demonstrating more prominent residual components/lack of response following treatment. Conclusions:18F-DOPA PET provides useful information for evaluating the metabolism of DIPGs. T/S ratio is an independent predictor of outcome. 18F-DOPA uptake extent delineates tumoral regions with a more aggressive biological behaviour, less sensitive to first line treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Tronco Encefálico/terapia , Quimioradioterapia/métodos , Glioma Pontino Intrínseco Difuso/terapia , Puente/diagnóstico por imagen , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biopsia , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/mortalidad , Niño , Preescolar , Cuerpo Estriado/diagnóstico por imagen , Glioma Pontino Intrínseco Difuso/diagnóstico , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidad , Dihidroxifenilalanina/administración & dosificación , Dihidroxifenilalanina/análogos & derivados , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Histonas/genética , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Mutación , Puente/patología , Tomografía de Emisión de Positrones , Estudios Retrospectivos , Medición de Riesgo/métodos , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiación , Vinorelbina/farmacología , Vinorelbina/uso terapéuticoRESUMEN
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain cancer. There has been no improvement in event-free survival (EFS) or overall survival (OS) despite immense effort through a multitude of clinical trials to find a cure. Recently, there has been a surge in the knowledge of DIPG biology, including the discovery of a recurrent H3F3A mutation in over 80% of these tumors. AREAS COVERED: The authors review the most recent approaches to diagnosis and treatment of DIPG including chemotherapy, biologics, surgical approaches, and immunotherapy. EXPERT OPINION: The authors propose four main opportunities to improve long-term survival. First, patients should be enrolled in scientifically sound clinical trials that include molecularly profiling either via stereotactic biopsy or liquid biopsy. Second, clinical trials should include more innovative endpoints other than traditional EFS and OS such as MRI/PET imaging findings combined with surrogates of activity (e.g. serial liquid biopsies) to better ascertain biologically active treatments. Third, innovative clinical trial approaches are needed to help allow for the rapid development of combination therapies to be tested. Finally, effort should be concentrated on reversing the effects of the histone mutation, as this malfunctioning development program seems to be key to DIPG relentlessness.
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Neoplasias del Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/terapia , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/mortalidad , Niño , Glioma Pontino Intrínseco Difuso/diagnóstico , Glioma Pontino Intrínseco Difuso/mortalidad , HumanosRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer whose median survival time is under one year. The possible roles of the two most common DIPG associated cytoplasmic ACVR1 receptor kinase domain mutants, G328V and R206H, are reexamined in the context of new biochemical results regarding their intrinsic relative ATPase activities. At 37 °C, the G328V mutant displays a 1.8-fold increase in intrinsic kinase activity over wild-type, whereas the R206H mutant shows similar activity. The higher G328V mutant intrinsic kinase activity is consistent with the statistically significant longer overall survival times of DIPG patients harboring ACVR1 G328V tumors. Based on the potential cross-talk between ACVR1 and TßRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several TßRI inhibitors on ACVR1 wild-type and G328V mutant patient tumor derived DIPG cell lines at 20-50 µM doses. SU-DIPG-IV cells harboring the histone H3.1K27M and activating ACVR1 G328V mutations appeared to be less susceptible to TßRI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as TßRI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.
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Receptores de Activinas Tipo I/genética , Neoplasias del Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/genética , Mutación/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Benzazepinas/farmacología , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Neoplasias del Tronco Encefálico/enzimología , Neoplasias del Tronco Encefálico/mortalidad , Línea Celular Tumoral , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Glioma Pontino Intrínseco Difuso/enzimología , Glioma Pontino Intrínseco Difuso/mortalidad , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/farmacología , Panobinostat/farmacología , Fosfotransferasas/metabolismo , Pronóstico , Conformación Proteica , Pirimidinas/farmacología , Quinoxalinas/farmacología , Receptor Cross-Talk , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidoresRESUMEN
BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, -268.15 versus -26.11, P = .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression.
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Neoplasias del Tronco Encefálico/diagnóstico por imagen , Glioma Pontino Intrínseco Difuso/diagnóstico por imagen , Neuroimagen/métodos , Neuroimagen/normas , Adolescente , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benchmarking , Bencimidazoles/administración & dosificación , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/terapia , Quimioradioterapia/métodos , Niño , Glioma Pontino Intrínseco Difuso/mortalidad , Glioma Pontino Intrínseco Difuso/terapia , Progresión de la Enfermedad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Interpretación de Imagen Asistida por Computador/normas , Imagen por Resonancia Magnética/métodos , Masculino , Imagen de Perfusión/métodos , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Temozolomida/administración & dosificaciónRESUMEN
BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a devastating childhood cancer that despite being primarily diagnosed by MR imaging alone, lacks robust prognostic imaging features. This study investigated patterns and quantification of extrapontine lesion extensions as potential prognostic imaging biomarkers for survival in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: Volumetric analysis of baseline MR imaging studies was completed in 131 patients with radiographically defined typical diffuse intrinsic pontine gliomas. Extrapontine tumor extension was classified according to the direction of extension: midbrain, medulla oblongata, and right and left middle cerebellar peduncles; various extrapontine lesion extension patterns were evaluated. The Kaplan-Meier method was used to estimate survival differences; linear regression was used to evaluate clinical-radiographic variables prognostic of survival. RESULTS: At least 1 extrapontine lesion extension was observed in 125 patients (95.4%). Of the 11 different extrapontine lesion extension patterns encountered in our cohort, 2 were statistically significant predictors of survival. Any extension into the middle cerebellar peduncles was prognostic of shorter overall survival (P = .01), but extension into both the midbrain and medulla oblongata but without extension into either middle cerebellar peduncle was prognostic of longer overall survival compared with those having no extension (P = .04) or those having any other pattern of extension (P < .001). CONCLUSIONS: Within this large cohort of patients with typical diffuse intrinsic pontine gliomas, 2 specific extrapontine lesion extension patterns were associated with a significant overall survival advantage or disadvantage. Our findings may be valuable for risk stratification and radiation therapy planning in future clinical trials.
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Neoplasias del Tronco Encefálico/diagnóstico por imagen , Neoplasias del Tronco Encefálico/patología , Glioma Pontino Intrínseco Difuso/diagnóstico por imagen , Glioma Pontino Intrínseco Difuso/patología , Adolescente , Neoplasias del Tronco Encefálico/mortalidad , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/mortalidad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
PURPOSE: Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG. EXPERIMENTAL DESIGN: We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations. RESULTS: We uncover TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53MUT cells. CONCLUSIONS: Here, we demonstrate that TP53 mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.
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Neoplasias del Tronco Encefálico/metabolismo , Glioma Pontino Intrínseco Difuso/metabolismo , Tolerancia a Radiación , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/radioterapia , Ciclo Celular/genética , Ciclo Celular/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidad , Glioma Pontino Intrínseco Difuso/radioterapia , Relación Dosis-Respuesta en la Radiación , Técnicas de Silenciamiento del Gen , Histonas/genética , Histonas/metabolismo , Humanos , Mutación , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de la radiación , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/genética , Tolerancia a Radiación/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. RESULTS: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. CONCLUSIONS: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
Asunto(s)
Glioma Pontino Intrínseco Difuso/metabolismo , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismo , Tolerancia a Radiación , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Benzazepinas/farmacología , Línea Celular Tumoral , Daño del ADN , Reparación del ADN/efectos de los fármacos , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidad , Glioma Pontino Intrínseco Difuso/radioterapia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Femenino , Recombinación Homóloga , Humanos , Ratones , Pronóstico , Pirimidinas/farmacología , Tolerancia a Radiación/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.