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: 10469346
• 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/10469346
• 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; 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.

慢性脊髓细胞性白血病（CMML）是白血病的致命亚型，其特征是细胞质的特征， 骨髓发育不良，单核细胞增多症和转化为急性髓样白血病（AML）的倾向。 在最具侵略性的慢性大麻恶性肿瘤中，中位生存率为34个月 CMML的突变已在影响镀铬状态的40多个基因中，mRNA剪接， 不幸的是，造血分化和细胞因子信号通路。 在CMML中鉴定出的遗传改变，尚未开发出疗法以改善 CMML的自然历史差。 模型尚未概括人类疾病的独特临床或组织学特征。 使用免疫功能低下的小鼠创建了急性白血病的患者衍生的Xenograph（PDX） 宿主可以准确地对该疾病进行建模并已用于体内认证推定的假定韧带。 但是，到目前为止，对于CMML的PDX模型的开发一直是有限的 组已经克服了这一限制，并产生了CMML的高度和遗传准确的PDX模型 通过使用几种新型的改性点数/scIDIL2RNULL（NSG）小鼠菌株表达Humang 此外，我们还使用这些PDX模型来识别唯一的CMML的细胞因子 靶向CMML的特定遗传亚集中的异常细胞因子信号特性和mRNA剪接。 在此提案中，我们旨在进一步定义模型对人类状况的保真度，并测试几个 新颖的临床前治疗方法，具有以下内容的IMEDIATE转换性，如下所示：在AIM 1中 我们将严格探索通过确定是否与他们各自患者进行比较的PDX模型的保真度 PDX模型概括了CMML的整个临床，转录和蛋白质组学光谱 确定CMML PDX模型是否可以使用使用患者对JAK2抑制剂的特异性反应 来自我们完成的JAK1/2抑制剂ruxolitinib cml中的I/II期临床试验的样品和A 前瞻性2 ruxolitinib cmml临床研究； 基于剪接体基因突变的CMML PDX中剪接体调节化合物的作用 状态。 目前缺乏临床前模型的侵略性癌症模型。 相关性是我们的研究将确定这种情况的新疗法 目前的治疗。