Medical Research

This study will perform a proof of concept study to determine the optimal strategy for comprehensively characterizing somatic genetic events in individual tumors with a focus on grade II pediatric astrocytoma. We anticipate that these studies will determine the important oncogenes and tumor suppressor genes that drive pediatric low-grade glioma development.  We also anticipate that an understanding of the molecular pathways disrupted by these mutations will guide the development of rational therapeutics for this disease.    If successful, it will enable rapid followup with an extended characterization of larger numbers of tumors to identify the recurrent events that cause this disease.

Much excitement in the low-grade astrocytoma field has been generated by the discovery of frequent mutations in a protein kinase known as “BRAF”.  However these BRAF mutations can account for only ~ one third of these pediatric tumors.  The PLGA program at Dana-Farber is focusing on genetic lesions that underlie the remaining two thirds of these tumors.  Towards this end, we are creating a dedicated core facility for a technology known as Chromatin Immune Precipitation Sequencing (“ChIP/Seq”).  The ChIP/Seq method identifies potentially druggable genetic targets for DNA-binding proteins known as “transcription factors”.   The ChIP method will be used to identify genetic targets for  three transcription factors plus the Olig2 transcription factor which  may play an even

In the fullness of time, small molecule inhibitors of BRAF may be used for the treatment of BRAF mutant pediatric LGAs. However, multiple protein kinases have been shown to be co-activated in high-grade adult gliomas, and this is likely to be the case in BRAF-transformed pediatric astrocytomas as well. Complimentary signaling pathways are both an obstacle and an opportunity for targeted therapy strategies.

The PLGA Foundation is already supporting a doctorate level scientist to create mouse models of low-grade astrocytoma and to conduct entry-level tests on these cells for drugs that may benefit children with LGAs.  However, to this point all of our drug testing has been conducted on cells grown in the laboratory in plastic culture dishes.  Some of these cell models (and some of the drugs we have tested “in vitro”) now show some promise.  This grant will take the next steps in testing cell for drugs outside the culture dish.

For the first time in 17 years, the SIOP meeting is returning to the United States.  This meeting brings together an interdisciplinary group of over 2000 clinical pediatric oncologists from all over the world. 

The Low Grade Glioma Symposium will feature talks as follows:

-  Surgical Approaches to the Treatment of Low-Grade Gliomas,  R. Michael Scott, United States
-  Modern Radiotherapy,  Torunn Yock, United States
-  Low-Grade Glioma in Children: Molecular Genetics and Novel Systemic Therapies, Olaf Witt, Germany
-  Optic Pathway Glioma: How Can we Optimize Outcomes, David Walker, United Kingdom

The symposium will be conducted on Friday, October 22nd from 10:30 - 12:00 pm.  

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