Exploiting the Metabolic Dependencies of Pediatric AML

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The Candidate: I am well-positioned to become an independent academic physician-scientist and expert in hematologic malignancies' metabolic dependencies. My commitment to improving cure-rates and decreasing treatment toxicities for my pediatric acute myeloid leukemia (AML) patients drives me. We have already optimized cytotoxic chemotherapy to its tolerability limit. So, to meaningfully improve pediatric AML outcomes— a devastating disease with a ~50% mortality rate—we must identify and target AML-blast dependencies. Our lab found that the proven, well-tolerated drug atovaquone (AQ) has anti-leukemia effects. This led me to design and conduct a limited-institution trial to (1) assess how to incorporate AQ into upfront pediatric AML treatment regimens and (2) collect biospecimens to use in my AQ experiments. The trial has also enabled the just-opened Children's Oncology Group Phase III trial to collect data on AQ use in newly diagnosed AML patients. My goal is to pinpoint the mechanism by which AQ targets leukemia cells and understand and target the metabolic pathways that sustain them. I am committed to uncovering these pathways to better treat pediatric AML. Career Development Plan: My data demonstrating that AQ significantly suppresses AML blasts' oxidative phosphorylation (OXPHOS) has shaped my career goals. My mentorship team and the Texas Medical Center's abundant resources, including Baylor College of Medicine's (BCM) graduate programs, will help me learn to precisely target AML blasts' dysregulated metabolism. I will meet frequently with my primary mentor, Dr. Sreekumar, to review data from my Aim 1a experiments and discuss results with my expert scholarship oversight committee. My secondary mentor, Dr. Redell, will continue helping me navigate the Children's Oncology Group`s complexities. BCM and my division will provide 75% protected research time and start-up funds in my K08 award's 4th year. I will then vie for an R01 focused on targeting pediatric AML blasts' dysregulated metabolism. Research Plan: My work suggests that AQ induces apoptosis by inhibiting the electron transport chain's complex III, thereby inhibiting OXPHOS. I hypothesize that OXPHOS suppression triggers the integrated stress pathway (ISR) resulting in progression to cell death. We now know that chemotherapy-resistant AML cells depend upon OXPHOS and that adult AML patients who take AQ for pneumonia have fewer relapses. To test my hypothesis, I will use focused techniques to evaluate AML-cells' metabolic dependencies and AQ's impact on them. I will use CRISPR-Cas9 gene-editing and our patient-derived xenografts to determine how soluble factors known to promote chemotherapy-resistance augment AQ-induced apoptosis and to better understand which patients might most benefit from treatments targeting OXPHOS dependency. I will measure AQ-induced apoptosis in a large patient sample cohort and identify an AQ-sensitivity signature by comparing RNAseq- generated sensitive- and resistant-sample transcriptomes. Understanding AML blasts' dysregulated metabolism will form a strong foundation on which to build my career and help find better treatments for children with AML.