Targeting amino acid metabolism and pyrimidine synthesis to overcome acute myeloid leukemia chemoresistance

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Response to chemotherapy is common, but cure is not in AML and many other cancer types. Overcoming persisting cell chemoresistance is a critical issue in improving the outlook for patients. The Scadden laboratory has hypothesized and shown that AML cells in vivo pass through a unique metabolic state induced by the therapy and surrounding cell death. To do so, they developed a work stream for selecting AML cells at particular times followed by untargeted metabolomics on the isolated cells. Distinct metabolomics were defined in AML cells during the window of maximal stress following induction chemotherapy with an unanticipated and distinctive diversion of glutamine metabolism toward pyrimidine metabolism in persisting cells. This dependency was validated in vivo by inhibiting pyrimidine synthesis in a timed manner that improved animal survival. My goal is to advance these findings to primary human AML cells using patient-derived xenograft (PDX) lines. First, I will verify pyrimidine synthesis as metabolic dependency also in human leukemia. Second, I will evaluate a combination of brequinar as an inhibitor of the enzyme dihydroorotate dehydrogenase with other metabolically active substances (asparaginase, venetoclax, azacitidine) based on the distinct metabolic vulnerabilities at the moment of maximal response. Third, I will compare the effect of brequinar following induction therapy in primary and relapsed PDX post-chemotherapy. Fourth, I will investigate the effect of amino acid depletion and inhibition of pyrimidine synthesis on leukemia stem cells and test the sensitivity of normal hematopoietic stem and progenitor cells toward our approach. Confirming and targeting the metabolic vulnerabilities in human leukemia might block the cellular program that enables AML cells to defy induction chemotherapy. Consequently, a timed inhibition of amino acid uptake and pyrimidine synthesis can exploit this critical therapeutic window in antineoplastic therapy and reduce the risk of relapse of the disease.