Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Brain Stem Neoplasms / genetics*
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Brain Stem Neoplasms / mortality
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Brain Stem Neoplasms / pathology
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Brain Stem Neoplasms / therapy
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Checkpoints / radiation effects
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Cell Proliferation / drug effects
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Cell Proliferation / radiation effects
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / genetics*
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors
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Cyclin-Dependent Kinase 6 / genetics*
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Cyclin-Dependent Kinase 6 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / deficiency
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Disease Models, Animal
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Drug Administration Schedule
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Gamma Rays
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / radiation effects
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Glioma / genetics*
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Glioma / mortality
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Glioma / pathology
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Glioma / therapy
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Mice
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Oncogene Proteins, Fusion / deficiency
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Oncogene Proteins, Fusion / genetics
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Piperazines / pharmacology*
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Proto-Oncogene Proteins c-sis / genetics
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Proto-Oncogene Proteins c-sis / metabolism
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Pyridines / pharmacology*
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Signal Transduction
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Survival Analysis
Substances
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Antineoplastic Agents
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Oncogene Proteins, Fusion
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Piperazines
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Proto-Oncogene Proteins c-sis
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Pyridines
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Retinoblastoma Protein
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Cdk4 protein, mouse
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Cdk6 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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palbociclib