Ph1/2 Study of the Imipridone ONC201 for Treatment of AML IND125,203 (12/23/2014)

咪啶酮 ONC201 治疗 AML IND125,203 的 Ph1/2 研究 (12/23/2014)

• 批准号: 9806956
• 负责人: MICHAEL ANDREEFF
• 金额: $ 25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9806956
• 关键词: Ph1; Study; Imipridone; ONC201; Treatment

Project Summary/Abstract Survival rates (app. 30 %) of acute myeloid leukemia (AML) have not been improved over 4 decades, except in some specialized instances. The long term aim of this study is to increase the cure rates of AML through clinical implementation of targeting a new cellular survival mechanism, i.e. mitochondrial (mt) unfolded protein response (mtUPR). We are proposing to conduct a clinical Phase 1/2 trial of ONC201, a first-in-class imipridone and to confirm and further investigate the underlying novel mechanism of action (MOA). We discovered in extensive preclinical studies that ONC201 induces apoptosis in AML but not in normal cells. Importantly, ONC201 has great efficacy in p53-mutated AML, the most chemotherapy-resistant subset, as well as in p53 wild-type AML. Our preclinical studies further demonstrate that ONC201 eliminates functionally- defined leukemia stem cells in patient-derived xenografts. Early trials initiated at MD Anderson show excellent tolerability of ONC201, micromolar plasma concentrations, and early clinical responses. We previously reported that ONC201 induces apoptosis mediated by the transcription factor ATF4, a hallmark of integrated stress response (ISR). However, ONC201 did not induce all characteristic molecular changes associated with classical ISRs (e.g., ER stress), suggesting an atypical MOA to induce ATF4. As break through progress reported in this re-submission, we have discovered that ONC201 directly binds and activates the mitochondrial protease, ClpP, resulting in selective mitochondrial proteolysis. The resultant reduction of mt protein pools induces so-called mt protein folding stress (mtPFS) and the protective transcriptional response against mtPFS termed mt unfolded protein response (mtUPR). Importantly, ATF4 is known to be induced through mtUPR, connecting our previous findings on ATF4 in a way different from classical ISRs. We here hypothesize that AML progenitor and stem cells are more susceptible to mtPFS than normal cells, and that ONC201 is targeting a novel point of vulnerability in AML pathobiology. The proposed clinical trial in leukemia provides a unique opportunity to thoroughly investigate this hypothesis. We will conduct a Phase 1/2 study of ONC201 in AML (Aim 1), and evaluate the underlying MOA (Aim 2). The Phase 1 trial will determine the safety and preliminary efficacy of ONC201 and Phase 2 the overall response rate. Changes in ATF4, mtUPR effector proteins, mt function and biogenesis in AML cells will be investigated using standard immunoblot and PCR methods as well as novel tools including CyTOF (single cell proteomics). We will also determine if ClpP, ATF4 and mtUPR effector proteins are potential biomarkers of clinical response to ONC201. Changes in clonal architecture will be monitored by flow cytometry and single-cell DNA sequencing. Genome-wide RNAseq will also be performed to further elucidate MOA and potential resistance. We expect these studies, which are at the cutting edge of our evolving knowledge of mitochondrial pathophysiology, to be developed into a highly effective and novel concept for the treatment of AML.

项目概要/摘要 4 年来，急性髓系白血病 (AML) 的生存率（约 30%）没有得到改善，除了 一些特殊的实例。本研究的长期目标是通过以下方式提高 AML 的治愈率： 针对新的细胞生存机制，即线粒体（mt）未折叠蛋白的临床实施 响应（mtUPR）。我们提议对 ONC201 进行临床 1/2 期试验，ONC201 是一流的 咪啶酮并确认并进一步研究潜在的新作用机制（MOA）。我们 在广泛的临床前研究中发现，ONC201 会诱导 AML 细胞凋亡，但不会诱导正常细胞凋亡。 重要的是，ONC201 对 p53 突变的 AML（化疗耐药性最强的亚型）也具有出色的疗效 如 p53 野生型 AML。我们的临床前研究进一步证明 ONC201 消除了功能性- 在患者来源的异种移植物中定义了白血病干细胞。 MD 安德森癌症中心启动的早期试验显示出良好的效果 ONC201 的耐受性、微摩尔血浆浓度和早期临床反应。我们之前 报道称 ONC201 诱导由转录因子 ATF4 介导的细胞凋亡，这是整合的标志 应激反应（ISR）。然而，ONC201 并没有诱导与相关的所有特征性分子变化。 经典 ISR（例如 ER 应激），表明非典型 MOA 可以诱导 ATF4。随着突破的进步 在此重新提交的报告中，我们发现 ONC201 直接结合并激活线粒体 蛋白酶 ClpP，导致选择性线粒体蛋白水解。由此导致的 mt 蛋白池减少 诱导所谓的 mt 蛋白折叠应激 (mtPFS) 和针对 mtPFS 的保护性转录反应 称为 mt 未折叠蛋白反应 (mtUPR)。重要的是，已知 ATF4 是通过 mtUPR 诱导的， 以不同于经典 ISR 的方式连接我们之前对 ATF4 的发现。我们在这里假设 AML 祖细胞和干细胞比正常细胞更容易受到 mtPFS 的影响，而 ONC201 的目标是 AML 病理学中的一个新的脆弱点。拟议的白血病临床试验提供了独特的 有机会彻底研究这个假设。我们将进行 ONC201 治疗 AML 的 1/2 期研究 （目标 1），并评估底层 MOA（目标 2）。第一阶段试验将确定安全性和初步结果 ONC201的疗效和2期总体缓解率。 ATF4、mtUPR 效应蛋白、mt 的变化 还将使用标准免疫印迹和 PCR 方法研究 AML 细胞的功能和生物合成 作为包括 CyTOF（单细胞蛋白质组学）在内的新颖工具。我们还将确定 ClpP、ATF4 和 mtUPR 是否 效应蛋白是 ONC201 临床反应的潜在生物标志物。克隆结构的变化将 通过流式细胞术和单细胞 DNA 测序进行监测。还将进行全基因组 RNAseq 进一步阐明 MOA 和潜在的耐药性。我们期待这些处于前沿的研究 我们不断发展的线粒体病理生理学知识将被开发成一种高效且新颖的方法 治疗 AML 的概念。