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，髓系肿瘤与 化疗和/或电离辐射是公众健康的重大问题。临床数据显示 与治疗相关的髓系肿瘤(t-MNS)患者的预后很差，有5年的 存活率为10%。T-MNS对标准癌症治疗的不良反应很大程度上是由于 肿瘤抑制基因P53的突变。已有研究表明，p5 3突变型t-mns 通过扩增携带预先存在的p53突变的罕见的肿瘤启动细胞。因此， 该项目的总体目标是通过抑制p53突变型t-MNS的发展 肿瘤起始细胞的扩增和/或在癌前阶段选择性地杀死肿瘤起始细胞 舞台。为了选择性地靶向p53突变细胞，我们将使用临床上使用的小分子药物APR-246 通过恢复野生型p53的构象和功能来重新激活突变的p53蛋白的试验。我们 假设APR-246治疗将阻止遗传毒性应激诱导的P53的扩张 突变的HSPC和选择性地杀死p53突变的HSPC，这些突变的HSPC在基因毒性治疗后已经扩张。 我们将使用我们开发的一种新的小鼠模型来验证这一假设，在该模型中，罕见的HSPC 表达p53R172H突变的两人在全身照射后经历细胞扩增 具体目标：目标1-评估APR-246治疗在全身照射中对 P53突变型HSPC的扩增及AIM 2--检测APR-246联合阿扎替丁的杀伤作用 P53突变型HSPC经全身照射后扩增。我们预计结果是 从这项概念验证R03拨款将生成可重现的数据，以支持对 利用APR-246或其他突变型p53激活剂将癌症患者t-MNS的风险降至最低 显示了肿瘤抑制基因P53的克隆性造血突变。

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.