Project 5: Targeting Oxidative Phosphorylation in AML

项目摘要/摘要 急性髓系白血病(AML)包括一组遗传和临床上不同的 侵袭性血液系统恶性肿瘤。尽管在AML的分子特征方面取得了进展，但 大多数患者会复发并死于他们的疾病。在急性髓细胞白血病中，氧化磷酸化(OxPhos) 产生促进生长和支持所需的细胞内能量和代谢中间产物 生死存亡。与正常的造血干细胞不同，AML和白血病干细胞(LCS)过表达抗- 凋亡线粒体蛋白Bc l-2，依赖OxPhos，无法利用糖酵解时 线粒体呼吸受到抑制，表明线粒体功能的维持 对急性髓系白血病的生存至关重要。 我们已经确定了一种新的有效的OxPhos(OxPhosi)IACS-010759的纳米分子抑制剂， 从1,000多种不同结构类别的化合物中挑选出来。IACS-010759 已发现能抑制OxPhos呼吸链的复合体I并阻断氧消耗。我们的数据 在AML细胞株和AML细胞株中显示出显著的生长抑制和促凋亡作用 原代AML细胞在低NM浓度下，对正常BM细胞的毒性最小。反过来, OxPhos抑制剂与Bcl2抑制剂联合应用对急性髓系白血病有协同作用。每日给药 Iacs-010759在小鼠体内耐受性良好，在体内异种移植研究中显示出很强的疗效。 利用人急性髓系白血病患者来源的异种移植物(PDX)和减少表型定义的LSC 用新的质量细胞仪技术--CyTOF测定组分。氧磷脂的给药情况 标准化疗延长了原发AML PDX模型的存活期。IACS的I期临床试验- 010759复发性/难治性急性髓系白血病最近在MDACA启动。 我们建议检验这样一种假设，即抑制OxPhos构成一种新的治疗方法 针对急性髓系白血病独特的代谢脆弱性的方法；以及联合封锁 OxPhos和Bcl-2抑制剂的线粒体呼吸将消除白血病启动细胞和 产生客观的反应。我们将在体外建立包括RNA在内的对OxPhosi反应的生物标志物 和代谢组学特征，在一大系列具有已知遗传特征的原发AML中，并验证 这些都在体内的AML PDX模型中。我们将进一步确定AML细胞协同作用的机制 文尼替克阻断Bcl2诱导OxPhos抑制后死亡及抗AML的特征 以及该组合的抗LSC效果。我们将进一步对存活的AML细胞进行代谢分析 标准化疗，并测试OxPhosi将减少或消除残余存活的假设 急性髓系白血病细胞。这些概念将被转化为标准化疗和Bc l-2期研究的1/2期研究。 2抑制剂万托克拉司联合IACS-010759治疗复发/难治性急性髓细胞白血病

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) comprises a genetically and clinically heterogeneous group of aggressive hematological malignancies. Despite advances in molecular characterization of AML, the majority of patients will relapse and die of their disease. In AML, oxidative phosphorylation (OxPhos) generates intracellular energy and metabolic intermediates necessary to promote growth and support survival. Unlike normal hematopoietic stem cells, AML and leukemia stem cells (LCS) overexpress anti- apoptotic mitochondrial protein Bcl-2, rely on OxPhos and are unable to utilize glycolysis when mitochondrial respiration is inhibited, indicating that the maintenance of mitochondrial function is essential for AML survival. We have identified a novel potent nanomolar inhibitor of OxPhos (OxPhosi) IACS-010759, selected from the series of more than 1,000 compounds across distinct structural classes. IACS-010759 has been found to inhibit complex I of OxPhos respiratory chain and block oxygen consumption. Our data demonstrated profound growth-inhibitory and pro-apoptotic effects of this agent in AML cell lines and primary AML cells at low nM concentrations, with minimal toxicity against normal BM cells. In turn, combination of OxPhos inhibitors and Bcl-2 inhibitor venetoclax is synergistic in AML. Daily dosing of IACS-010759 was well tolerated in mice, demonstrated strong efficacy in the in vivo xenograft studies utilizing the human AML patient-derived xenografts (PDX) and reduced phenotypically defined LSC fractions measured by novel technique of mass cytometry, CyTOF. Administration of OxPhosi following standard chemotherapy extended survival in primary AML PDX model. A Phase I clinical trial of IACS- 010759 in relapsed/refractory AML was recently launched at MDACC. We propose to test the hypothesis that OxPhos inhibition constitutes a novel therapeutic approach that targets a unique metabolic vulnerability of AML; and that combined blockade of mitochondrial respiration by OxPhos and Bcl-2 inhibitors will eliminate leukemia-initiating cells and produce objective responses. We will establish biomarkers of response to OxPhosi in vitro including RNA and metabolomics signatures, in a large series of primary AML with known genetic profiling, and validate these in the in vivo AML PDX models. We will further determine mechanisms of synergistic AML cell death when OxPhos inhibition is primed by Bcl-2 blockade with venetoclax, and characterize anti-AML and anti-LSC efficacy of such combination. We will further metabolically profile AML cells surviving standard chemotherapy, and test the hypothesis that OxPhosi will reduce or eliminate residual surviving AML cells. These concepts will be translated into Phase 1/2 study of standard chemotherapy and of Bcl- 2 inhibitor Venetoclax combined with IACS-010759 in patients with relapsed/refractory AML.