Human iPSC PLGA Models for Drug Discovery

Award: $300,000 over 3 years (2019-2022)
Principle Investigators: Dr. David Gutmann, The Washington University in St. Louis

Pediatric low-grade astrocytomas (PLGAs) are benign brain tumors that have proven difficult to maintain as cell lines in vitro or as patient-derived xenografts in vivo. These obstacles reflect numerous critical features that distinguish PLGAs from their malignant counterparts. First, these tumors have low proliferative indices and frequently undergo senescence. Second, PLGAs are highly dependent on trophic support from non-neoplastic (stromal) cells in the tumor microenvironment, such as microglia and lymphocytes. Third, these tumors likely arise from a limited number of progenitor populations. Lastly, many PLGAs, especially those located within midline structures, are not biopsied or resected. Because of these barriers, there are few successful human PLGA models for preclinical drug identification, therapeutic agent testing, and biomarker discovery. Leveraging human induced pluripotent stem cell engineering, we have successfully generated tractable human PLGA models for basic science investigation and preclinical application. The overarching goal of this project is to develop and characterize a series of human PLGA models that reflect the genetic diversity of these brain tumors in children.