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

摘要 由于癌症幸存者的数量不断增加，与癌症相关的骨髓肿瘤 化疗和/或电离辐射是公众健康的重要关注点。临床数据表明 治疗相关性髓系肿瘤（t-MN）患者的结局较差，5年 生存率10%。t-MN对标准癌症治疗的不利反应主要是由于 肿瘤抑制基因p53的突变已经证明，p53突变型t-MN是由 通过扩增携带预先存在的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t-MN的发生来防止p53突变t-MN的发生。 肿瘤起始细胞的扩增和/或通过选择性杀死癌前病变的肿瘤起始细胞 阶段为了选择性地靶向p53突变细胞，我们将使用APR-246，一种小分子药物， 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 假设用APR-246治疗将防止遗传毒性应激诱导p53扩增 突变型HSPC和选择性杀死在遗传毒性治疗后扩增的p53突变型HSPC。 我们将使用我们开发的一种新的小鼠模型来测试这一假设，在这种模型中，罕见的HSPC 表达p53 R172 H突变的小鼠在暴露于全身照射后经历细胞扩增， 具体目的：目的1 -评价全身照射期间APR-246治疗对 p53突变体HSPC的扩增和目的2 -检查APR-246加阿扎胞苷对杀伤的作用 p53突变型HSPC在全身照射后扩增。我们预计， 从这个概念验证R 03赠款将产生可重复的数据，支持进一步调查， 利用APR-246或其它突变型p53激活剂使患有t-MN的癌症患者的风险最小化， 显示肿瘤抑制基因p53突变的克隆造血。

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.