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NIH grant 1K08CA297049-01A1: Targeting metabolic drivers of therapy resistance in TP53 mutant acute myeloid leukemia
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Sarah J Skuli. Award: $298701.
Start: 2026-09-18T00:00:00.
PROJECT SUMMARY
Below we have provided an updated abstract that addresses utilization of vertebrate animals in this proposal.
The goal of the proposed five-year training plan is the development of my independent research career as an academic physician-scientist studying therapy refractory acute myeloid leukemias (AML). I am specifically seeking to develop and refine the skills that will be required to successfully transition to independence, including genetic manipulation, bioinformatics, and pre-clinical therapeutic development. Under the guidance of my research mentors, Dr. Martin Carroll and Dr. Celeste Simon, at the University of Pennsylvania (UPENN), I have developed a structured training plan consisting of intensive laboratory research, didactics, and oversight by an experienced faculty advisory committee. I will have the full resources of UPENN available for the completion of the K08. The proposed research will focus on metabolic dependencies in the archetype of refractory AML harboring TP53 mutations (TP53mut AML). Leveraging comprehensive analyses, I have uncovered a critical role of the mevalonate pathway, specifically its downstream byproduct geranylgeranyl pyrophosphate (GGPP), in mediating resistance to cytarabine (AraC), a cornerstone AML chemotherapeutic.
Specifically, GGPP is required for an adaptive AraC metabolic phenotype involving increased antioxidant synthesis and mitochondrial mass/activity. Successful translation to clinical trials will require a deeper understanding of the timecourse of the GGPP-dependent metabolic phenotype in vivo and elucidation of the specific function of GGPP in chemoresistance. In the following aims, I will explore these gaps in knowledge with novel, isogenic rp53mut AML cell lines and primary human samples in vitro and in vivo.
Xenotransplantation mouse models are essential for these studies because they represent the most clinically predictive preclinical model of human AML and are required to evaluate therapeutic efficacy, leukemic burden, and dynamic metabolic adaptations within the physiologic in vivo microenvironment. Animal studies will be limited to the minimum number necessary to achieve statistically rigorous results, and multiple experimental endpoints will be obtained from individual animals whenever possible. In Aim 1, I will establish the temporal dynamics of the AraC metabolic adaptations in vivo with transcriptomics/metabolomics and target it with a novel GGPP transferase inhibitor, GGTl2418. I anticipate that rp53mut primary AML will be chemoresistant in vivo and gene expression/metabolites will demonstrate a biphasic response of antioxidant synthesis and mitochondrial biogenesis. Furthermore, I expect that combination GGTl2418 and AraC will synergistically reduce leukemic burden in POX models of TP53mut AML with GGTl2418 administration required during the window of the adaptive metabolic phenotype. To understand the specific mechanisms by which the mevalonate pathway contributes to chemoresistance/metabolism and expand the pool of novel therapeutic targets, in Aim 2 I will define the critical role of GGPP that canonically functions in post-translational modification of GTPases. I identified the RhoA GTPase and 5 RhoA partners as essential for rp53mut AML in a CRISPR screen evaluating GTPases/regulators. In Aim 2, I will evaluate mevalonate pathway-dependent RhoA GTPase activity following AraC treatment and subsequently use genetic/pharmacological knockdown to determine the role of RhoA in chemoresistance in vitro and in vivo. Successful completion of this career development award will leave me uniquely prepared to establish my independent career as a physician-scientist studying metabolic drivers of chemoresistance in refractory AML.document fetched 2026-09-26 02:42