Developing and credentialing patient-derived xenograft models to advance therapeutic approaches for chronic myelomonocytic leukemia

开发和认证患者来源的异种移植模型，以推进慢性粒单核细胞白血病的治疗方法

• 批准号: 10226881
• 负责人: Eric Padron
• 金额: $ 49.66万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226881
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Affect; Binding; Biological Assay; Characteristics; Chromatin; Chronic; Chronic Myelomonocytic Leukemia; Clinical; Clinical Research; Clinical Trials; Credentialing; Cytokine Signaling; Dependence; Development; Disease; Disease model; Dysplasia; Gene Mutation; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Health; Hematopoietic Neoplasms; Histologic; Human; Human Characteristics; IL2RA gene; Immunocompromised Host; JAK1 gene; JAK2 gene; Knockout Mice; Malignant Neoplasms; Marrow; Messenger RNA; Methodology; Modeling; Monocytosis; Mouse Strains; Mus; Mutation; Myeloproliferative disease; Natural History; Patients; Phase; Phase I/II Clinical Trial; Phenotype; Pre-Clinical Model; Proteome; Proteomics; RNA; RNA Splicing; Recurrence; Sampling; Signal Pathway; Signaling Protein; Testing; Therapeutic; Time; Tissue Banks; Xenograft procedure; base; cancer cell; curative treatments; cytokine; cytopenia; effective therapy; experience; hematopoietic differentiation; human disease; improved; in vivo; inhibitor/antagonist; leukemia; mouse model; mutational status; nano-string; new therapeutic target; non-genetic; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; patient response; phase 2 study; pre-clinical; predicting response; prospective; response; screening; success; therapeutic target; transcriptome

Chronic Myelomonocytic Leukemia (CMML) is a lethal subtype of leukemia characterized by cytopenias, marrow dysplasia, monocytosis, and a propensity for transformation to acute myeloid leukemia (AML). It is among the most aggressive chronic myeloid malignancies with a median survival of 34 months. Recurrent mutations in CMML have been identified in over 40 genes affecting chromatin state, mRNA splicing, hematopoietic differentiation, and cytokine signaling pathways. Unfortunately, despite the increasing number of genetic alterations identified in CMML, no therapies have been developed with the potential to improve the poor natural history of CMML. Moreover, attempts to model CMML using genetically engineered mouse models have not recapitulated the unique clinical or histological characteristics of the human disease. Patient-derived xenografts (PDX) of acute leukemias have been created using immunocompromised mouse hosts that accurately model the disease and have been used to credential putative therapeutic targets in vivo. However, until now, there has been limited success with development of PDX models for CMML. Recently, our groups have overcome this limitation and generated highly and genetically accurate PDX models of CMML through the use of several novel modified NOD/SCID IL2R null (NSG) mouse strains expressing human cytokines that uniquely drive CMML. Moreover, we have utilized these PDX models to identify novel therapies targeting aberrant cytokine-signaling characteristics and mRNA splicing in specific genetic subsets of CMML. In this proposal we aim to further define the fidelity of these models to the human condition and test several novel preclinical therapeutic approaches with immediate translatability to CMML patients as follows: In Aim 1 we will rigorously explore the fidelity of our PDX models compared to their respective patients by determining if PDX models recapitulate the entire clinical, transcriptional, and proteomic spectrum of CMML ; Aim 2 will determine whether CMML PDX models can recapitulate patient-specific responses to JAK2 inhibitors using samples from both our completed phase I/II clinical trial of the JAK1/2 inhibitor ruxolitinib in CMML and a prospective phase 2 ruxolitinib CMML clinical study; Aim 3 will determine the efficacy and mechanism of action of spliceosomal modulatory compounds in CMML PDXs based on spliceosomal gene mutation status. The significance of these studies is that they will create genetically and phenotypically accurate models of an aggressive form of cancer that is lacking preclinical models currently. Moreover, the health relatedness is that our studies will identify novel therapies for this condition, which lacks any effective therapies currently.

慢性粒单核细胞白血病（CMML）是一种以血细胞减少为特征的致死性白血病亚型， 骨髓发育不良、单核细胞增多和转化为急性髓性白血病（AML）的倾向。是 在最具侵袭性的慢性髓系恶性肿瘤中，中位生存期为34个月。复发性 CMML中的突变已经在超过40个影响染色质状态，mRNA剪接， 造血分化和细胞因子信号传导途径。不幸的是，尽管越来越多的 尽管在CMML中发现了遗传改变，但尚未开发出具有改善CMML的潜力的疗法。 CMML的自然史较差。此外，尝试使用基因工程小鼠模型CMML， 模型不能概括人类疾病的独特临床或组织学特征。 已经使用免疫功能低下的小鼠产生了急性白血病的患者来源的异种移植物（PDX）。 准确模拟疾病的宿主，并已用于确认体内推定的治疗靶点。 然而，到目前为止，CMML的PDX模型的开发取得了有限的成功。最近我们 研究小组已经克服了这一限制，并产生了高度和遗传准确的CMML PDX模型 通过使用几种新的修饰的NOD/SCID IL 2 R敲除（NSG）小鼠品系表达人IL 2 R， 唯一驱动CMML的细胞因子。此外，我们还利用这些PDX模型来确定新的治疗方法， 靶向CMML特定遗传亚群中的异常精氨酸信号传导特征和mRNA剪接。 在这项提案中，我们的目标是进一步定义这些模型对人类状况的保真度，并测试几个 新的临床前治疗方法，可立即转化为CMML患者，如下所示： 我们将严格探索我们的PDX模型与其各自患者相比的保真度， PDX模型概括了CMML的整个临床、转录和蛋白质组谱;目标2将 确定CMML PDX模型是否可以重现患者对JAK 2抑制剂的特异性反应， 来自我们完成的JAK 1/2抑制剂ruxolitinib治疗CMML的I/II期临床试验和 前瞻性II期鲁索利替尼CMML临床研究;目的3将确定 基于剪接体基因突变的剪接体调节化合物在CMML PDX中的作用 status.这些研究的意义在于，它们将创造出在基因和表型上准确的 目前缺乏临床前模型的侵袭性癌症的模型。此外，健康 我们的研究将为这种缺乏有效治疗的疾病找到新的治疗方法， 治疗目前。