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New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis.

ABSTRACT: Diffuse Instrinsic Pontine Glioma is the most aggressive form of High Grade Gliomas in children. The lack of biological material and the absence of relevant models have hampered the development of new therapeutics. Their extensive infiltration of the brainstem renders any surgical resection impossible and until recently biopsies were considered not informative enough and therefore not recommended. Thus, most models were derived from autopsy material. We aimed to develop relevant in vivo DIPG models that mimic this specific disease and its molecular diversity from tumor material obtained at diagnosis. Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain. These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease.

SUBMITTER: Plessier A

PROVIDER: S-EPMC5581049 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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New <i>in vivo</i> avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis.

Plessier Alexandre A Le Dret Ludivine L Varlet Pascale P Beccaria Kévin K Lacombe Joëlle J Mériaux Sébastien S Geffroy Françoise F Fiette Laurence L Flamant Patricia P Chrétien Fabrice F Blauwblomme Thomas T Puget Stéphanie S Grill Jacques J Debily Marie-Anne MA Castel David D

Oncotarget 20170202 32

Diffuse Instrinsic Pontine Glioma is the most aggressive form of High Grade Gliomas in children. The lack of biological material and the absence of relevant models have hampered the development of new therapeutics. Their extensive infiltration of the brainstem renders any surgical resection impossible and until recently biopsies were considered not informative enough and therefore not recommended. Thus, most models were derived from autopsy material. We aimed to develop relevant <i>in vivo</i> D ...[more]

PMID: 28881750

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Project description:Abstract PURPOSE: To correlate MR imaging findings with molecular analyses in DIPG. METHODS: Baseline MR imaging studies, including standard pre- and post-contrast MR sequences, were reviewed from patients included in our multi-institutional, IRB-approved DIPG trial NCT01182350. Prospectively acquired imaging data were analyzed after study closure, including FLAIR/T2 tumor volume; tumor volume enhancement and cyst/necrosis; median, mean, mode, skewness, and kurtosis of apparent diffusion coefficient (ADC) tumor volume based on both FLAIR and enhancement at baseline. Whole-genome and RNA-sequencing identified histone mutations. We applied univariate Cox proportional-hazards regression modeling to test the association of imaging predictors with overall (OS) and progression-free survival (PFS). Wilcoxon rank-sum, Kruskal-Wallis, and Fisher’s exact tests compared imaging measures between groups. RESULTS: Fifty patients underwent biopsy and MRI. Median age at trial registration was 6 years (range,3.3–17.5 years); 52% of patients were female. Molecular subgroup study assignments for 48 patients’ tumors were as follows: 28 in MGMT-/EGFR-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Further genetic testing identified mutations in histones, PDGFRA, ACVR1, TP53, EGFR, PPM1D, FGFR, and/or PI3K. Twenty-three tumors possessed histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HISTH3C. Median follow-up time was 11 months (range,0.4–33 months). Poorer OS (p=0.01) and PFS (p=0.001) were significantly associated with increased enhancing tumor volume. Enhancing tumor volume also differed significantly across molecular subgroups (p=0.047). Tumor enhancement, mode, skewness, and kurtosis ADC-FLAIR differed significantly (p?0.048) between patients with H3F3A and HIST1H3B mutations. Tumor enhancement, median, mode, skewness, and kurtosis ADC-FLAIR also differed significantly (p?0.048) between patients with H3F3A and HIST1H3B or HISTH3C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters correlate to molecular subgroups in DIPG. Further studies are required to verify and refine these findings in a larger cohort.

Project description:Abstract Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. The objective of this study was to evaluate the suitability of DNX-2401 as treatment for pHGG/DIPGs. Our results showed that DNX-2401 exerts a potent antitumor effect in pHGG (n=5) and DIPG (n=6) cell lines in vitro and in vivo. Our clinical trial experience with DNX-2401 in adult glioblastoma underscored the importance of the immune system in durable responses observed in patients. DNX-2401 administration in two DIPG immunocompent models was safe and without toxicity. DNX-2401 prolonged the overall survival, leading 20% to 80% of long-term survivors. Histologic examination showed that DNX-2401 stimulated T-cell infiltration (CD3+, CD4+ and CD8+; p<0.001) within the tumor. Esplenocytes from DNX-2401 treated-mice co-cultured with tumor cells significantly increase the IFNg production (p<0.0001). These outstanding preclinical results allowed us to open a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. Up to date 7 patients have been treated within the trial (3x1010viral particles in 1mL). The procedure was well tolerated and safe. Patients were home 3–4 days after the procedure. All the patients displayed a reduced tumor volume after combined treatment. In the next weeks, we will have information regarding the median survival. We are currently conducting molecular and functional studies to assess the response of the patients to the virus. Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumor patients.

Dataset Information

New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis.

Publications

New <i>in vivo</i> avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis.

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