Targeting PLK1 in RAS mutant chronic myelomonocytic leukemia

RAS 突变型慢性粒单核细胞白血病中的靶向 PLK1

基本信息

批准号：
10656778
负责人：
Mrinal Shiv Patnaik
金额：
$ 42.71万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656778
关键词：
Acute Myelocytic Leukemia Apoptosis Biological Assay Biology Body Weight Changes Bone Marrow CBL gene Cell Death Cell Proliferation Cells ChIP-seq Chronic Myelomonocytic Leukemia Classification Clinical Clinical Trials Code Combined Modality Therapy Data Development Disease Dose Down-Regulation Drug Kinetics Epigenetic Process Event Foundations Frequencies Future Gene Expression Gene Expression Profile Genes Genetic Genotype Hematologic Neoplasms Hematopoietic Neoplasms Histologic Hour Hypersensitivity In Vitro Individual KRAS2 gene Knockout Mice Laboratories MEKs MLL gene Maximum Tolerated Dose Mitosis Mitotic Checkpoint Mitotic spindle Mononuclear Mutation Myeloproliferative disease NF1 gene Oncogenic Oral Outcome PLK1 gene PTPN11 gene Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase I Clinical Trials Phosphorylation Phosphotransferases Proteins RAF1 gene RNA Interference RNA interference screen Recommendation Refractory Regulation Relapse Research Resistance Risk Role Safety Sampling Seminal Signal Transduction Spleen TPT1 gene Time Toxic effect Variant White Blood Cell Count procedure Work Xenograft procedure biobank biomarker driven clinical efficacy cohort combinatorial design effective therapy genetic variant genome-wide in vivo in vivo Model inhibitor innovation leukemic transformation mutant novel novel therapeutic intervention overexpression patient derived xenograft model personalized therapeutic pharmacologic phase I trial phase II trial predicting response progenitor response safety testing survival outcome synergism targeted treatment therapeutic target transcriptome sequencing transcriptomics treatment strategy tumor growth

项目摘要

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.

项目摘要慢性脊髓细胞性白血病（CMML）是一种侵略性的血液系统恶性肿瘤，结果令人沮丧。对CMML的理性衍生疗法有未满足的需求。 CMML可以分为 “增生性”（PCMML）和“发育不良”亚型，PCMML具有高频RAS途径突变和中位生存期为<18个月。我们已经在PCMML中表明突变的NRA是一个真正的致癌驱动力，RAS途径突变与独特富含有丝分裂检查点激酶（如PLK1）的基因表达谱。 PLK1是最高的蛋白质编码基因在RAS突变体CMML中进行了更新，鉴于先前的RNAi研究表明 RAS突变细胞对PLK1抑制的敏感性提高了，PLK1与 RAF1处于有丝分裂纺锤体，以及在AML试验中持续使用临床级PLK1抑制剂，我们选定的PLK1作为RAS突变体PCMML的治疗靶标。我们显示了RAS的不同灵敏度使用体外（祖细胞分析）和体内模型（患者 - 衍生的Xenographictics）并证明了与低甲基化剂（HMA）的潜在协同作用。我们现在提出第二阶段1临床试验测试Onvansertib的安全性和初步效果，这是一种新颖的口服PLK1 使用创新的Boin（贝叶斯最佳间隔）的继电器/难治性PCMML患者的抑制剂设计。试验患者的样本将用于评估药代动力学，靶向效率和反应与PLK1和KMT2A（RAS PLK1轴调节剂）表达水平的相关性。我们还将使用我们的大型 CMML生物座（n = 177个RAS突变样品）在体外和体内模型中发展，以评估突变，反应和抗性的转录组和表观遗传学预测指标；特别是单个RAS的影响途径突变以及tet2和ASXL1突变，这两个定义的两个最常见的响应 CMML突变，onvansertib响应。根据我们的初步数据，我们的中心假设是 PLK1抑制是RAS突变体PCMML的有效治疗策略，响应受到影响定义的突变特征和表观遗传特征。我们将首先执行一个阶段来解决这一假设 1临床试验测试口服选择性PLK1抑制剂Onvansertib的安全性和靶向效率 PCMML（目标1）。其次，我们将确定单个RAS途径突变的体外影响和相关的CMML转录组和表观遗传谱在Onvansertib响应上（AIM 2）。最后，我们会的评估ASXL1/TET2突变对Onvansertib和Onvansertib的反应的影响途径突变体CMML异种移植物（AIM 3）。如果成功，这项研究将为您提供第一个针对性的治疗 Ras突变髓样肿瘤，为血液学个性化治疗奠定了基础恶性肿瘤。