Latest Research: “Functionally defined therapeutic targets in diffuse intrinsic pontine glioma”. Published in Nature Medicine, May 2015
Grasso CS1, Tang Y2, Truffaux N3, Berlow NE4, Liu L5, Debily MA6, Quist MJ1, Davis LE7, Huang EC7, Woo PJ5, Ponnuswami A5, Chen S5,Johung TB5, Sun W8, Kogiso M9, Du Y9, Qi L9, Huang Y10, Hütt-Cabezas M11, Warren KE12, Le Dret L3, Meltzer PS12, Mao H9, Quezado M12, van Vuurden DG13, Abraham J7, Fouladi M14, Svalina MN15, Wang N1, Hawkins C16, Nazarian J17, Alonso MM18, Raabe EH11,Hulleman E13, Spellman PT1, Li XN9, Keller C19, Pal R4, Grill J20, Monje M5.
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