Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations

通过抑制基因毒性应激诱导的 p53 突变白血病起始细胞的扩增，最大限度地降低治疗相关的骨髓肿瘤的风险

• 批准号: 10310505
• 负责人: Chang-Lung Lee
• 金额: $ 8.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310505
• 关键词: Acute Myelocytic Leukemia; Appearance; Azacitidine; Cancer Patient; Cancer Survivor; Cell Death; Cells; Chemotherapy and/or radiation; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clonal Expansion; DNA; Data; Development; Dominant-Negative Mutation; Dysmyelopoietic Syndromes; Exposure to; Future; Genotoxic Stress; Goals; Grant; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Impairment; Investigation; Ionizing radiation; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Molecular Conformation; Mutation; Myeloproliferative disease; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase I/II Clinical Trial; Population; Primary Neoplasm; Proteins; Public Health; Radiation therapy; Refractory Neoplasm; Reporter; Reproducibility; Research; Risk; Sampling; TP53 gene; Testing; Tumor Expansion; Whole-Body Irradiation; cancer therapy; clinically relevant; deep sequencing; driver mutation; effective therapy; experimental study; fitness; genotoxicity; high risk; leukemia initiating cell; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; pre-clinical; premalignant; prevent; rare cancer; response; risk minimization; small molecule; therapy development; treatment response; tumor

ABSTRACT Due to an ever-increasing number of cancer survivors, myeloid neoplasms associated with chemotherapy and/or ionizing radiation are a significant concern for public health. Clinical data indicate that the outcome for patients with therapy-related myeloid neoplasms (t-MNs) is poor, with a 5-year survival of 10%. The unfavorable response of t-MNs to standard cancer therapies is largely due to mutations in the tumor suppressor p53. It has been demonstrated that p53 mutant t-MNs are developed through the expansion of rare tumor-initiating cells harboring pre-existing p53 mutations. Therefore, the overall goal of this project is to prevent the development of p53 mutant t-MNs by inhibiting the expansion of tumor-initiating cells and/or by selectively killing tumor-initiating cells at the premalignant stage. To selectively target p53 mutant cells, we will use APR-246, a small molecule drug in clinical trials that reactivates mutant p53 protein by restoring wild-type p53 conformation and function. We hypothesize that treatment with APR-246 will prevent the genotoxic stress-induced expansion of p53 mutant HSPCs and selectively kill p53 mutant HSPCs that have expanded after genotoxic therapies. We will test this hypothesis using a novel mouse model that we have developed in which rare HSPCs expressing a p53R172H mutation undergo cell expansion after exposure to total-body irradiation in two specific aims: Aim 1 – Evaluate the impact of APR-246 treatment during total-body irradiation on the expansion of p53 mutant HSPCs and Aim 2 – Examine the effect of APR-246 plus azacitidine on killing p53 mutant HSPCs that have expanded after total-body irradiation. We anticipate that the outcomes from this proof-of-concept R03 grant will generate reproducible data that support further investigation of utilizing APR-246 or other mutant p53 activators to minimize the risk of t-MNs in cancer patients who show clonal hematopoiesis of mutations in the tumor suppressor p53.

抽象的 由于癌症幸存者数量不断增加，与骨髓瘤相关的 化疗和/或电离辐射是公共卫生的一个重大问题。临床数据表明 治疗相关性骨髓瘤 (t-MN) 患者的预后较差，5 年生存期 存活率10%。 t-MN 对标准癌症治疗的不利反应很大程度上是由于 抑癌基因 p53 突变。已证明 p53 突变 t-MN 已形成 通过扩增含有预先存在的 p53 突变的罕见肿瘤起始细胞。因此， 该项目的总体目标是通过抑制p53突变体t-MNs的发展 肿瘤起始细胞的扩增和/或通过在癌前选择性地杀死肿瘤起始细胞 阶段。为了选择性地靶向p53突变细胞，我们将使用临床上的小分子药物APR-246 通过恢复野生型 p53 构象和功能来重新激活突变型 p53 蛋白的试验。我们 假设 APR-246 治疗将阻止基因毒性应激诱导的 p53 扩增 突变 HSPC 并选择性杀死基因毒性治疗后扩增的 p53 突变 HSPC。 我们将使用我们开发的一种新型小鼠模型来检验这一假设，该模型中含有稀有的 HSPC 表达 p53R172H 突变的细胞在两次暴露于全身照射后经历细胞扩增 具体目标： 目标 1 – 评估全身照射期间 APR-246 治疗对 p53 突变体 HSPC 的扩增和目标 2 – 检查 APR-246 加阿扎胞苷对杀伤作用的影响 全身照射后扩增的 p53 突变 HSPC。我们预计结果 从这个概念验证 R03 拨款中将产生可重复的数据，支持进一步调查 利用 APR-246 或其他突变 p53 激活剂来最大限度地降低癌症患者发生 t-MN 的风险 显示肿瘤抑制因子 p53 突变的克隆造血作用。