Utilizing Brain Tumor Microenvironment to Propagate Pediatric Pilocytic Astrocytoma in Vitro and Test Novel Targeted Drug Therapies

Abstract

Pediatric brain tumors have recently surpassed leukemia as the leading cause of cancer related death in children (American Brain Tumor Association). Pilocytic astrocytoma (PA) is the most common type of primary central nervous system tumor in children. Although these low-grade tumors have a high survival rate, the surgery and treatment required for PA can cause lasting neurological deficits. Furthermore, unlike many high-grade tumor types, PA tumor cells have yet to be successfully grown and propagated in vitro or via xenografts. This has prevented researchers from testing drug therapies on actual human tumor cells and limited the studies to less clinically relevant PA mouse models. Given that majority of PA tumors that express the oncogenic fusion mutation KIAA1549:BRAF and develop in the cerebellum, it is possible that the infratentorial brain microenvironment uniquely supports PA tumor growth. The goals of this thesis research were to: 1) develop a novel, in vitro, three-dimensional hydrogel co-culture system that mimics the infratentorial brain microenvironment to grow and propagate PA tumor cells, 2) investigate the efficacy of using this system as a method for testing novel therapeutics on human PA tumor cells. The results from this research show that PA tumor cells prefer to grow in the infratentorial brain microenvironment, and that infratentorial astrocytes alter PA oncogenic pathway activity in vitro. These studies also indicate that the hydrogel co-culture assay can be utilized to grow a variety of types of LGGs, including PA, long term. Additionally, inhibitor testing in the hydrogel co-culture assay may be an effective method for drug testing on human and mouse model PA cells.