PROJECT SUMMARY Nanoparticle-based therapies have many potential advantages for treating cancer, but there are currently no clinical biomarkers to predict which patients are most likely to benefit from nanotherapeutics over conventional anticancer agents. To improve the efficacy of nanoparticles for cancer treatment, I will investigate nanoparticle drug delivery in the context of SLC46A3, a liposome-specific biomarker recently identified in a massively parallel pooled cancer cell line screen. Based on strong preliminary data, I hypothesize that SLC46A3 plays a role in phospholipid metabolism in cancer cells, making it a therapeutically relevant biomarker for liposomal nanotherapeutics. This proposal aims to establish the role of SLC46A3 in phospholipid homeostasis and directly connect SLC46A3 expression to therapeutic liposome delivery in vivo using pediatric neuroblastoma as a model system. The ultimate goal of the project is to validate SLC46A3 as a clinical biomarker for liposomal nanoparticle delivery and develop rigorous preclinical data to motivate biomarker-stratified clinical trials for both existing, FDA- approved liposomes and experimental formulations. I am a pediatric oncologist seeking K08 support for a mentored training period under the co-mentorship of Dr. Paula Hammond at the Massachusetts Institute of Technology (MIT) and Dr. Kimberly Stegmaier at Dana-Farber Cancer Institute/Boston Children’s Hospital (DFCI/BCH). My long-term career goal is to be an independent physician-scientist, studying nano-bio interfaces and interactions with the goal of advancing nanomedicine to the clinic for cancer patients. My prior research experiences have established my skills in nanomedicine and drug delivery. I am now well positioned to establish the necessary expertise in cancer metabolism and functional genomics through the critical mentored K08 award. The DFCI/BCH, MIT and the Broad Institute of MIT and Harvard are internationally recognized research programs with a number of expert researchers in the areas of functional genomics, metabolism and nanomaterials, among others. The DFCI Division of Pediatric Oncology has a distinguished record of training young physician-scientists for leadership roles in pediatric cancer research. I have assembled an excellent mentoring and advisory committee, consisting of Dr. Matthew Vander Heiden (MIT), Dr. Angela Koehler (MIT), and Dr. Steven Dubois (DFCI), who will guide my research and training experiences along with my mentors. With structured mentoring, educational, and scientific plans, I will acquire the necessary expertise to become a successful independent investigator in translational cancer nanomedicine.