RESEARCH ARTICLE SPOTLIGHT: (October 2015) “Functionally defined therapeutic targets in diffuse intrinsic pontine glioma”. Published in Nature Medicine, May 2015

Latest Research: “Functionally defined therapeutic targets in diffuse intrinsic pontine glioma”. Published in Nature Medicine, May 2015

Grasso CS1Tang Y2Truffaux N3Berlow NE4Liu L5Debily MA6Quist MJ1Davis LE7Huang EC7Woo PJ5Ponnuswami A5Chen S5,Johung TB5Sun W8Kogiso M9Du Y9Qi L9Huang Y10Hütt-Cabezas M11Warren KE12Le Dret L3Meltzer PS12Mao H9Quezado M12van Vuurden DG13Abraham J7Fouladi M14Svalina MN15Wang N1Hawkins C16Nazarian J17Alonso MM18Raabe EH11,Hulleman E13Spellman PT1Li XN9Keller C19Pal R4Grill J20Monje M5.

Summary:

In an international collaboration led by Dr. Michelle Monje, Dr. Charles Keller, Dr. Ranadip Pal and Dr. Jacques Grill, The DIPG Preclinical Consortium recently published results aimed at identifying the most promising therapeutic agents for DIPG.  Eighty-three cancer drugs were selected by an international group of pediatric neuro-oncologists; these agents were screened against a panel of 16 patient-derived DIPG cell lines. DIPG cells exhibited particular sensitivity to 14 of the 83 drugs, including several cell cycle inhibitors (SNS-032, alvocidib, dinaciclib), two histone deacetylase (HDAC) inhibitors (panobinostat, vorinostat), a PI3K/mTOR inhibitor (BEZ235), and a proteasome inhibitor (AUY922).  Computational predictive modeling based on drug screen and RNA-sequencing data was used to identify the most potent drug in vitro, and panobinostat was chosen for further study.  Panobinostat was tested in patient-derived xenografts using convection-enhanced and systemic delivery at various doses and schedules. Panobinostat-treated mice demonstrated decreased tumor size and prolonged survival compared to control mice. Since chronic administration of panobinostat DIPG cells demonstrated resistance to the drug, potential combination therapies were also studied.  Panobinostat showed no synergy with the alkylating agent temozolomide but demonstrated potent synergy with DNA demethylase inhibitor, GSK-J4 (a compound that is unfortunately not currently in preclinical development).  In mice, panobinostat was found at clinically-effective concentrations in the pons after system administration, suggesting its potential to cross the blood-brain barrier. Based on these preclinical data, panobinostat will soon be available to children with recurrent DIPG as part of an early phase clinical trial through the Pediatric Brain Tumor Consortium.

Link to full publication: http://rdcu.be/eu80

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