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Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

SUBMITTER: Grasso CS

PROVIDER: S-EPMC4862411 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

Grasso Catherine S CS Tang Yujie Y Truffaux Nathalene N Berlow Noah E NE Liu Lining L Debily Marie-Anne MA Quist Michael J MJ Davis Lara E LE Huang Elaine C EC Woo Pamelyn J PJ Ponnuswami Anitha A Chen Spenser S Johung Tessa B TB Sun Wenchao W Kogiso Mari M Du Yuchen Y Qi Lin L Huang Yulun Y Hütt-Cabezas Marianne M Warren Katherine E KE Le Dret Ludivine L Meltzer Paul S PS Mao Hua H Quezado Martha M van Vuurden Dannis G DG Abraham Jinu J Fouladi Maryam M Svalina Matthew N MN Wang Nicholas N Hawkins Cynthia C Nazarian Javad J Alonso Marta M MM Raabe Eric H EH Hulleman Esther E Spellman Paul T PT Li Xiao-Nan XN Keller Charles C Pal Ranadip R Grill Jacques J Monje Michelle M

Nature medicine 20150504 6

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the tw ...[more]

PMID: 25939062

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Project description:Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II-IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III-IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II-IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.

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Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

Publications

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

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