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

对化疗的反应是常见的，但在AML和许多其他类型的癌症中无法治愈。克服持续的细胞化疗耐药是改善患者前景的关键问题。Scadden实验室假设并证明体内AML细胞通过治疗和周围细胞死亡诱导的独特代谢状态。为此，他们开发了一个在特定时间选择AML细胞的工作流程，然后对分离的细胞进行非靶向代谢组学。在诱导化疗后的最大应激窗口期间，AML细胞中定义了不同的代谢组学，在持续细胞中，谷氨酰胺代谢出乎意料地向嘧啶代谢转移。这种依赖性通过抑制嘧啶合成在一定时间内提高动物存活率而在体内得到验证。我的目标是利用患者来源的异种移植物（PDX）系将这些发现推进到原代人AML细胞中。首先，我将验证嘧啶合成在人类白血病中也是代谢依赖性。其次，我将根据最大反应时刻的不同代谢脆弱性，评估作为二氢羟酸脱氢酶抑制剂的布雷奎那与其他代谢活性物质（天冬酰胺酶、venetoclax、阿扎胞苷）的组合。第三，我将比较布雷奎那在原发性和复发性化疗后PDX诱导治疗后的效果。第四，我将研究氨基酸缺失和嘧啶合成抑制对白血病干细胞的影响，并测试正常造血干细胞和祖细胞对我们方法的敏感性。确认和靶向人类白血病的代谢脆弱性可能会阻断使AML细胞抵抗诱导化疗的细胞程序。因此，定时抑制氨基酸摄取和嘧啶合成可以在抗肿瘤治疗中利用这一关键的治疗窗口，并降低疾病复发的风险。

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.