Identifying Novel Glioma Therapeutic Targets Using an Ecosystems Approach

Principal Investigator: GUTMANN, DAVID H
Institution Receiving Award: WASHINGTON UNIVERSITY
Program: NFRP
Proposal Number: NF120032
Award Number: W81XWH-13-1-0094
Funding Mechanism: Investigator-Initiated Research Award - Optional Qualified Collaborator
Partnering Awards:
Award Amount: $916,011.00


Rationale/Objective: Optic gliomas are the most common brain tumor arising in people affected with neurofibromatosis type 1 (NF1). The fact that these low-grade cancers arise in young children whose brains are continuing to develop and mature poses a significant barrier to treatment using DNA-damaging chemotherapy designed to treat adults with high-grade cancers. It is therefore not surprising that our current treatments have long-term harmful effects on the pediatric brain. Recent insights from our laboratories using novel Nf1 genetically engineered mouse strains have revealed that NF1-associated optic pathway gliomas (NF1-OPG) are composed of both cancerous and non-cancerous cell types, which cooperate with one another to facilitate tumor formation and growth. These critical observations have enabled us to reconceptualize NF1-OPG as cooperative cellular societies (ecosystems) and to begin to discover therapies that specifically target the cells and signals unique to the NF1-OPG ecosystem. In this proposal, we plan to leverage advanced microscopy technologies, unique Nf1 genetically engineered mouse strains, and individual cell molecular analysis methods to identify the key cells and signals that drive NF1-OPG growth.

Applicability: This proposal focuses on the most common brain tumor affecting individuals with NF1. The novel approach described in this application offers the potential to identify treatment strategies that target the cells and molecules unique to optic glioma, while sparing normal cells in the developing pediatric brain.

Contribution to NF Research and Clinical Care: The experiments and concepts outlined in this proposal are widely applicable to other benign tumors arising in NF1, including plexiform neurofibromas, and are likely to yield critical insights into the cellular and molecular drivers of NF1-OPG growth amenable to the design of more selective brain tumor treatments. Moreover, this approach may facilitate the development of therapies that spare the developing brains of children with NF1.