Developing Human Induced Pluripotent Stem Cell Precision Oncology Models

Abstract This proposal was specifically designed to support a dedicated Research Specialist with extensive experience in human induced pluripotent stem cell (hiPSC) engineering to study the cellular and molecular mechanisms underlying the formation and progression of central and peripheral nervous system tumors relevant to the identification of risk assessment and personalized therapeutic strategies. This investigator has longstanding expertise in RASopathy cancer predisposition syndromes, beginning with her doctoral studies focused on generating Cardio-Facial-Cutaneous and Costello Syndrome zebrafish preclinical models, and over the past ten years, initially as a postdoctoral fellow and now as an Assistant Professor on the Research track, in developing translational research tools for the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. As such, the Research Specialist established and continues to expand the Washington University NF Center hiPSC repository, which includes hiPSCs with patient-derived germline mutations, as well as engineered tagged or conditional knockout lines, explicitly designed to define the molecular and cellular etiologies underlying NF1- and RAS/MEK-associated nervous system cancers in children and adults. Leveraging the power of hiPSC engineering, this Research Specialist has pioneered work demonstrating that (1) NF1 mutations are not functionally equivalent in vitro or in vivo (cancer genetics), (2) NF1-mutant neurons drive low-grade nervous system tumor growth in an activity-dependent manner (cancer neuroscience), (3) neurons function as immune activators to establish an immune cell axis supportive of brain tumor growth (cancer immunology), (4) targeting neuronal excitability provides new options for the treatment of brain and nerve tumors (cancer therapeutics), (5) hiPSCs can be exploited to develop novel humanized models of low-grade brain and nerve tumors (cancer modeling), and (6) hiPSC cancer modeling revealed a chemokine circuit critical for patient-derived low-grade brain tumor xenograft generation (precision oncology). Moreover, multi-institutional international dissemination of these unique tools has galvanized new research directions within the Program Director’s laboratory, critical to the successful acquisition of new NCI grant funding and the establishment of new international collaborations. Finally, the Research Specialist’s commitment to the field, continued leadership in this scientific area, and critical importance in guiding hiPSC-based projects, both at Washington University and worldwide, will continue to provide clinically-actionable opportunities relevant to personalized risk assessment and medical management of people with RAS-related oncologic disease.