Novel combination therapy for AML expressing mutant RUNX1

表达突变体 RUNX1 的 AML 的新型联合疗法

基本信息

批准号：
10698087
负责人：
KAPIL BHALLA
金额：
$ 52.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10698087
关键词：
AML/MDS ATAC-seq Acute Myelocytic Leukemia Adult Age Architecture Biogenesis ChIP-seq Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex Core-Binding Factor Coupled DNA Binding Data Data Set Disease remission Dysmyelopoietic Syndromes Enrollment Epigenetic Process Familial Platelet Disorder Gene Expression Gene Expression Profile Genetic Germ-Line Mutation Guide RNA Harvest Hematopoiesis Homologous Transplantation Impairment In Vitro Lesion Libraries MCL1 gene Malignant - descriptor Maps Mediating Messenger RNA Molecular Mus Mutation Myeloproliferative disease Network-based Newly Diagnosed Outcome Patients Phase Ib/II Clinical Trial Phase Ib/II Trial Prognosis Progression-Free Survivals Protein Inhibition Proteins RUNX1 gene Recurrent disease Refractory Relapse Repression Research Resistance Ribosomes Risk Safety Science Tertiary Protein Structure Translations Treatment Protocols Xenograft Model Xenograft procedure acute myeloid leukemia cell analog attenuation autosome c-myc Genes chemotherapy co-clinical trial graft vs host disease high risk homoharringtonine improved in vivo in vivo Model inhibitor knock-down loss of function mutation mutant new therapeutic target next generation sequencing novel participant enrollment preclinical efficacy response small hairpin RNA targeted agent targeted treatment transcription factor transcriptome sequencing

项目摘要

With current treatment regimens, long-term remission rates for adult patients with high risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) are 15-25%. RUNX1 is the DNA- binding subunit of the core-binding factor (CBF) complex and a master-regulator transcription factor involved in hematopoiesis. Majority of mutant (mt) RUNX1 are missense, large deletions or truncation- mutations, behaving mostly as loss of function (LOF) mutations. Presence of mtRUNX1 confers relative therapy-resistance and poorer survival in patients with MDS/AML. The germline mutations and deletions in RUNX1 cause the highly penetrant (~40%) Familial Platelet Disorder with a propensity to evolve into MDS or AML. Lack of specific targeted therapy, coupled with resistance to standard therapy may account for poorer prognosis and outcome in MDS/AML expressing somatic or germline mtRUNX1. Therefore, there is an unmet need to develop novel targeted therapies for MDS/AML expressing mtRUNX1. Our preliminary studies demonstrate that knockdown of RUNX1 induces significantly more in vitro lethality in AML blasts expressing mtRUNX1 versus wild type (wt) RUNX1. Utilizing RNA-Seq signature of RUNX1 knockdown and querying the LINCS1000-CMap (Connectivity-Mapping) datasets, we identified homoharringtonine (HHT) among the top expression mimickers (EMs). Consistent with observations that presence of mtRUNX1 impairs ribosomal biogenesis (RiBi), treatment with HHT or its semisynthetic analog omacetaxine mepesuccinate (OM), which inhibit protein translation, preferentially exerted more lethality in vitro and efficacy in vivo in models of AML expressing mtRUNX1. This was associated with repression of RUNX1 and its targets, as well as attenuation of short-lived proteins including c-Myc and MCL-1. Notably, co-treatment with OM and venetoclax (Ven) induced synergistic lethality and superior in vivo efficacy in xenograft models of AML expressing mtRUNX1. Therefore, our Overarching hypothesis motivating studies proposed is that targeted combination of OM and Ven will yield high remission rates and improved survival, correlating with specific genetic and gene-expression signatures in patients with high-risk MDS/AML expressing mtRUNX1. Specific aims of studies proposed are: AIM 1: To conduct a Phase Ib/II clinical trial of co-treatment with OM and Ven in patients with high risk MDS or AML expressing mtRUNX1. AIM 2: To determine correlates of efficacy/resistance to co-treatment with OM and Ven, including genetic-lesions architecture (via NextGen and scDNA sequencing), epigenetic and gene- expression signature (via RNA-Seq, RPPA and CyTOF analyses) and impaired RiBi features in MDS/AML cells of patients enrolled on the Phase Ib/II trial. AIM 3: To determine pre-clinical efficacy of additional OM-based combinations with BET or CDK9 inhibitor, as well as with novel targeted agents directed against druggable hits nominated through an in vitro protein domain-specific CRISPR-gRNA screen.

根据目前的治疗方案，高危成年患者的长期缓解率骨髓增生异常综合征 (MDS) 和急性髓系白血病 (AML) 为 15-25%。 RUNX1 是 DNA- 核心结合因子 (CBF) 复合物的结合亚基和主调节转录因子参与造血作用。大多数突变体 (mt) RUNX1 是错义、大缺失或截短- 突变，主要表现为功能丧失（LOF）突变。 mtRUNX1 的存在赋予相对 MDS/AML 患者的治疗耐药性和较差的生存率。种系突变和缺失 RUNX1 中的 RUNX1 会导致高渗透性 (~40%) 家族性血小板疾病，并有可能演变成 MDS 或 AML。缺乏具体的靶向治疗，加上对标准治疗的抵抗可能是原因表达体细胞或种系 mtRUNX1 的 MDS/AML 的预后和结果较差。所以，对于表达 mtRUNX1 的 MDS/AML，开发新型靶向疗法的需求尚未得到满足。我们的初步研究表明，RUNX1 的敲低可显着提高体外致死率表达 mtRUNX1 的 AML 母细胞与表达野生型 (wt) RUNX1 的 AML 母细胞。利用 RUNX1 的 RNA-Seq 签名敲除并查询 LINCS1000-CMap（连接映射）数据集，我们确定了高三尖杉酯碱 (HHT) 属于顶级表达模仿者 (EM) 之列。与观察结果一致 mtRUNX1 的存在会损害核糖体生物合成 (RiBi)，用 HHT 或其半合成药物治疗类似物 omacetaxine mepesuccinate (OM)，抑制蛋白质翻译，优先发挥更多作用表达 mtRUNX1 的 AML 模型的体外致死率和体内功效。这与抑制 RUNX1 及其靶标，以及减弱短寿命蛋白，包括 c-Myc 和 MCL-1。值得注意的是，OM 和 Venetoclax (Ven) 联合治疗可诱导协同致死率，并且在表达 mtRUNX1 的 AML 异种移植模型的体内疗效。因此，我们的总体假设提出的激励性研究是 OM 和 Ven 的靶向组合将产生高缓解率并提高生存率，与患者的特定遗传和基因表达特征相关表达 mtRUNX1 的高风险 MDS/AML。拟议研究的具体目标是：目标 1：进行 OM 和 Ven 联合治疗高危 MDS 或 AML 表达患者的 Ib/II 期临床试验 mtRUNX1。目标 2：确定 OM 和 Ven 联合治疗的疗效/耐药性的相关性，包括遗传损伤结构（通过 NextGen 和 scDNA 测序）、表观遗传和基因损伤 MDS/AML 中的表达特征（通过 RNA-Seq、RPPA 和 CyTOF 分析）和 RiBi 特征受损参加 Ib/II 期试验的患者的细胞。目标 3：确定其他药物的临床前疗效基于 OM 与 BET 或 CDK9 抑制剂以及新型靶向药物的组合对抗通过体外蛋白质结构域特异性 CRISPR-gRNA 筛选提名的药物命中。