Targeting PLK1 in RAS mutant chronic myelomonocytic leukemia

项目总结 慢性粒单核细胞白血病(CMML)是一种侵袭性血液系统恶性肿瘤，预后不良。 CMML专注于理性衍生疗法的需求尚未得到满足。CMML可以分为 “增殖性”(PCMML)和“发育异常”亚型，其中pCMML具有高频率的RAS通路 突变并与中位生存期18个月有关。我们已经证明，在pCMML中， 突变的NRAS是真正的致癌驱动因素，RAS途径突变与独特的 基因表达谱富含有丝分裂检查点蛋白，如PLK1。PLK1位居榜首 蛋白编码基因在RAS突变体CMML中上调，并考虑到先前的RNAi研究表明 RAS突变细胞对PLK1抑制的敏感性增加以及PLK1与 在有丝分裂纺锤体的RAF1，以及在急性髓细胞白血病试验中临床级别PLK1抑制剂的持续使用，我们 在RAS突变体pCMML中选择PLK1作为治疗靶点。我们展示了RAS的微分敏感性 用体外(祖细胞集落试验)和体内模型(患者- 异种移植物)，并展示了与去甲基化药物(HMA)的潜在协同作用。我们现在提议 一项开创性的临床试验，测试新型口服PLK1 Onvansertib的安全性和初步疗效 在复发/难治性pCMML患者中使用一种创新的Boin(贝叶斯最佳间隔)抑制剂 设计。来自试验患者的样本将用于评估药物动力学、靶向疗效和反应。 与PLK1和KMT2A(RAS PLK1轴调节因子)表达水平的相关性。我们还将使用我们的大型 CMML生物信息库(n=177个RAS突变样本)，以开发体外和体内模型以评估突变， 反应和抗性的转录和表观遗传预测因子；特别是个体RAS的影响 途径突变和共存的TET2和ASXL1突变，这两种最常见的反应定义 CMML中的突变，对Onvansertib反应。根据我们的初步数据，我们的中心假设是 抑制PLK1是RAS突变体pCMML的有效治疗策略，其反应受 定义了突变特征和表观遗传学特征。我们将通过首先执行一个阶段来解决此假设 1临床试验测试口服选择性PLK1抑制剂Onvansertib的安全性和靶向性 PCMML(AIM 1)。其次，我们将确定单个RAS途径突变和 有关Onvansertib反应的CMML转录和表观遗传学特征(AIM 2)。最后，我们会 评估ASXL1/TET2突变对RAS-RAS细胞对Onvansertib和Onvansertib加HMA反应的影响 途径突变型CMML异种移植(AIM 3)。如果成功，这项研究将提供第一个靶向治疗 RAS突变的髓系肿瘤为血液学个性化治疗奠定了基础 恶性肿瘤。

PROJECT SUMMARY Chronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with dismal outcomes. There is an unmet need for CMML focused rationally derived therapies. CMML can be divided into “proliferative” (pCMML) and “dysplastic” subtypes, with pCMML having a high frequency of RAS pathway mutations and being associated with a median survival of <18 months. We have shown that in pCMML, mutant NRAS is a bona fide oncogenic driver and that RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic check point kinases such as PLK1. PLK1 was among the top protein coding genes upregulated in RAS mutant CMML and given that prior RNAi studies had shown increased sensitivity of RAS mutant cells to PLK1 inhibition and the fact that PLK1 physically interacts with RAF1 at the mitotic spindles, as well as the ongoing use of clinical grade PLK1 inhibitors in AML trials, we selected PLK1 as a therapeutic target in RAS mutant pCMML. We showed differential sensitivity of RAS mutant pCMML cells to PLK1 inhibition using in vitro (progenitor colony assays) and in vivo models (patient- derived xenografts) and demonstrated potential synergy with hypomethylating agents (HMA). We now propose a seminal Phase 1 clinical trial testing the safety and preliminary efficacy of Onvansertib, a novel, oral, PLK1 inhibitor in patients with relapsed/refractory pCMML, using an innovative BOIN (Bayesian Optimal Interval) design. Samples from trial patients will be used to assess pharmacokinetics, targeting efficacy and response correlations with PLK1 and KMT2A (regulator of RAS PLK1 axis) expression levels. We will also use our large CMML biorepository (n=177 RAS mutant samples) to develop in vitro and in vivo models to assess mutational, transcriptomic and epigenetic predictors of response and resistance; specifically the impact of individual RAS pathway mutations and cooccurring TET2 and ASXL1 mutations, the two most common response defining mutations in CMML, on Onvansertib responses. Based on our preliminary data, it is our central hypothesis that PLK1 inhibition is an effective treatment strategy in RAS mutant pCMML, with responses being influenced by defined mutational profiles and epigenetic features. We will address this hypothesis by first performing a Phase 1 clinical trial testing the safety and targeting efficacy of Onvansertib, an oral selective PLK1 inhibitor, in pCMML (AIM 1). Second, we will determine the in vitro impact of individual RAS pathway mutations and associated CMML transcriptomic and epigenetic profiles on Onvansertib responses (AIM 2). Finally, we will assess the impact of ASXL1/TET2 mutations on response to Onvansertib and Onvansertib plus HMA in RAS- pathway mutant CMML xenografts (AIM 3). If successful, this research will provide the first targeted therapy for RAS mutant myeloid neoplasms, setting the stage for personalized therapeutics in hematological malignancies.