Pediatrics & Therapeutics
Open Access

Novel-B RAF inhibitors as targeted therapeutics for pediatric low-grade astrocytoma

International Conference and Exhibition on Pediatric Oncology and Clinical Pediatrics

August 11-13, 2016 Toronto, Canada

Mark W Kieran, Yu Sun, Catherine Pilarz, David Calligaris, Emily J Chadwick, John A Alberta, Shakti H Ramkissoon, Lori A Ramkissoon, Veronica Matia Garcia, Kim Wilkinson, Michael Kane, Liliana Goumnerova, Nathalie Y Agar, Keith L Ligon, Rosalind A Segal, Levi A Garraway, Nathanael S Gray, Charles

Boston Children��?s Hospital at Harvard Medical School, USA

Posters & Accepted Abstracts: Pediat Therapeut

Abstract :

Introduction: Activating mutations in BRAF are identified in roughly 85% of all pediatric low-grade astrocytomas (PLGAs), either as the V600E point mutation (10%) or as a truncated fusion duplication (most commonly called the KIAA1549:BRAF). First generation RAF inhibitors approved for melanoma are only effective on tumors that express the canonical BRAFV600E oncoprotein. These drugs (type I antagonists that target the â�?�?DFG-inâ�? conformation of the kinase) fail to block signaling of other point mutations in BRAF as well as the KIAA1549: BRAF truncated fusion forms. In fact, these inhibitors result in activation of downstream signaling of the KIAA1549: BRAF forms due to a complex feedback loop. Purpose: We evaluated the activity of Type II RAF inhibitors (targeting the â�?�?DFG-outâ�? conformation of the kinase) in BRAF mutant and truncated fusion variants of pediatric low-grade gliomas. Methods: We developed pathway relevant model systems for the two major BRAF abnormalities seen in PLGAs for use as a drug screen in vitro andtumor response assay in vivo. In addition, an organoid ex vivo assay was developed to assess fresh tumor sample response to drugs. Mass spectroscopy imaging was also used to screen for those drugs that could penetrate the intact blood brain barrier. Results: A number of compounds were identified, including two different type II BRAF inhibitors that were capable of inhibiting downstream activation of pERK for both point mutations and the truncated fusion forms of BRAF. One compoundwas active on authentic human PLGA cells and also showed excellent CNS penetration. Based on these results, the first pediatric patient with a progressive low-grade astocytoma has undergone treatment with this agent. Conclusions: Type II BRAF inhibitors have a unique mechanism of action that results in broad inhibitory activity for both the different point mutations and common structural abnormalities of BRAF in pediatric low-grade gliomas.

Biography :

Email: mark_kieran@dfci.harvard.edu