$8.5 million over the next 5 years is the funding that will further the DFCI’s initial projects in three different critical basic science arenas. The long-term goal of this program is to improve the standard of care for pediatric astrocytomas – the most common brain cancers in children. Towards this end, we will improve our understanding of astrocytoma biology and develop new diagnostic, prognostic and therapeutic tools for these tumors. The significance of the work is that primary cancers of the central nervous system have now surpassed leukemia as the leading cause of cancer-related death in children. The grant will be utilized for three primary projects:
Project 1 draws upon recent observations of activating mutations in BRAF in ~50% of pediatric low grade astrocytomas and addresses three unresolved questions. William Hahn, MD/PhD and Jean Zhao, PhD will study: (i) what are the driving mutations in the ~50% of tumors wild type for BRAF, (ii) what are the mutations that co-occur with BRAF and (iii) what other intracellular kinases are co-activated with

BRAF? An innovative feature of this project is recently developed methods for genetic profiling of formaldehyde-fixed, paraffin-embedded samples. These paraffin-friendly technologies greatly expand the available samples of these pediatric tumors.

Project 2 addresses the bHLH transcription factor Olig2, with a chemical focus. Olig2 is a strong candidate for targeted therapy of pediatric astrocytomas. However, transcription factors are generally considered to be unattractive targets for drug development because their interactions with DNA involve large and complex surface area contacts. Another generic problem in brain tumor drug development is ensuring delivery beyond the blood/brain barrier. Charles Stiles, PhD and Loren Walensky, MD/PhD propose to develop specific inhibitors of Olig2 with good penetrance properties for the blood/brain barrier. Innovative features of this project are (i) ԓstapled peptide chemistry to create Olig2 antagonists used with (ii) MALDI mass spectrometry imaging technology to address drug penetrance into the interstitial areas of the brain.

Project 3 addresses the role of microenvironment in tumor growth. Rosalind Segal, MD/PhD has developed a novel assay for testing the effects of microenvironments on astrocytoma cells. In collaboration with neurosurgeon Liliana Goumerova, MD, she will use tumor cells from pediatric astrocytomas derived from different brain regions to determine whether tumor cells are ԓaddicted to the location where they originated, and whether tumor cell niches promote tumor growth, survival, and/or chemoattraction. These studies may lead to new strategies for disrupting the interface between astrocytoma cells and their niches. An innovative feature of this project is a consideration of cilia as signaling organelles that coordinate responses to the microenvironment.

The three projects interact with one another and are further unified by economies of scale enabled by an Innovative NeuroPathology (INP) core.

This grant represents a milestone for not just NCI supported research, but also reinforces the enormous results which are possible through public/private partnerships.Ԡ Prior to applying to the NCI for grant funding, all three projects described above were privately funded (through donations raised by the PLGA Foundation) and successfully tested at the DFCI’s PLGA Research program. Based on the successful outcomes from the projects, the NCI was able to support the next phase of each of these projects which will surely give researchers better direction in finding more effective treatments and a cure for PLGA. This model of public/private partnership is one which the PLGA Foundation seeks to replicate moving forward.

For more information on this NCI grant, please go to “Therapeutic Opportunities for PLGA