Novel combination therapy for AML expressing mutant RUNX1

表达突变体 RUNX1 的 AML 的新型联合疗法

• 批准号: 10276033
• 负责人: KAPIL BHALLA
• 金额: $ 53.42万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/10276033
• 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 Lines; Germ-Line Mutation; Guide RNA; Harvest; Hematopoiesis; Homologous Transplantation; Impairment; In Vitro; Lesion; Libraries; MCL1 gene; Malignant - descriptor; Mediating; Messenger RNA; Molecular; Mus; Mutation; Myeloproliferative disease; Network-based; Newly Diagnosed; Outcome; Patient risk; Patients; Phase Ib/II Clinical Trial; Phase Ib/II Trial; Prognosis; Progression-Free Survivals; Proteins; RUNX1 gene; Recurrent disease; Refractory; Relapse; Repression; Research; Resistance; Ribosomes; Safety; Science; Tertiary Protein Structure; Translations; Treatment Protocols; Xenograft Model; Xenograft procedure; acute myeloid leukemia cell; analog; attenuation; base; c-myc Genes; chemotherapy; co-clinical trial; graft vs host disease; high risk; homoharringtonine; improved; in vivo; in vivo Model; inhibitor/antagonist; knock-down; loss of function mutation; mutant; new therapeutic target; next generation sequencing; novel; preclinical efficacy; response; small hairpin RNA; targeted agent; targeted treatment; transcription factor; transcriptome sequencing

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.

使用当前的治疗方案，具有高风险的成年患者的长期缓解率 骨髓增生综合征（MDS）和急性髓性白血病（AML）为15-25％。 runx1是DNA- 核心结合因子（CBF）复合物和主调控因子的结合亚基 参与造血。大多数突变体（MT）Runx1是错义，大删除或截断 - 突变，主要是功能丧失（LOF）突变。 Mtrunx1的存在赋予了相对 MDS/AML患者的治疗耐药性和较差的存活率。种系突变和缺失 在runx1中导致高度渗透剂（约40％）家族血小板疾病，倾向于演变为 MDS或AML。缺乏特定的靶向疗法，再加上对标准疗法的抵抗力可能会说明 对于表达体细胞或种系Mtrunx1的MDS/AML的预后和预后较差和结果。所以， 对于MDS/AML表达MTRUNX1的新型靶向疗法有未满足的需求。我们的 初步研究表明，Runx1的敲低诱导了更多的体外杀伤力 表达MTRUNX1与野生型（WT）Runx1的AML爆炸。利用Runx1的RNA-Seq签名 敲低和查询lincs1000-cmap（连接映射）数据集，我们确定了 顶级表达模仿者（EMS）中的同伴（HHT）。与观察一致的 Mtrunx1的存在会损害核糖体生物发生（RIBI），用HHT或其半合成治疗 抑制蛋白质翻译的类似术甲酸甲酸甲酸酯（OM）优先施加更多 在AML表达mtrunx1模型中体内体外和功效的致死性。这与 抑制Runx1及其靶标，以及包括C-Myc和包括C-MYC在内的短寿命蛋白 MCL-1。值得注意的是，与OM和Venetoclax（VEN）共同治疗引起的协同致死性和优越性 AML表达mtrunx1的异种移植模型中的体内功效。因此，我们的总体假设 提出的激励研究是，OM和VEN的目标组合将产生高缓解率 并提高了生存率，与患者的特定遗传和基因表达信号相关 高风险MDS/AML表达MTRUNX1。提出的研究的具体目的是：目标1：进行 高风险MDS或AML表达的患者与OM和VEN共同治疗的IB/II期临床试验 mtrunx1。目标2：确定与OM和VEN共同治疗的功效/抗性相关性 包括遗传性质的结构（通过NextGen和ScDNA测序），表观遗传和基因 表达签名（通过RNA-SEQ，RPPA和CYTOF分析）和MDS/AML中的RIBI特征受损 参加IB/II期试验的患者细胞。目标3：确定额外的临床前功效 基于OM的BET或CDK9抑制剂的组合以及针对新的靶向剂的组合 针对通过体外蛋白质结构域特异性CRISPR-GRNA筛选提名的可药命中率。