SPORE in Myeloid Malignancies

骨髓恶性肿瘤中的孢子

• 批准号: 9755368
• 负责人: Benjamin Levine Ebert
• 金额: $ 213.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755368
• 关键词: Abnormal Cell; Acute Myelocytic Leukemia; Alleles; Award; Biological Assay; Biometry; Blood Cells; Bone Marrow Stem Cell; CLIA certified; Cancer Center; Cancer Etiology; Cells; Cellular biology; Chemistry; Clinical; Clinical Research; Clinical Trials; Correlative Study; Cytotoxic agent; Data; Development; Disease model; Dysmyelopoietic Syndromes; Ensure; Experimental Designs; Fostering; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Hospitals; Immune checkpoint inhibitor; Immune system; Immunodeficient Mouse; Immunology; Immunotherapeutic agent; JAK2 gene; K-Series Research Career Programs; Laboratories; Laboratory Research; Lead; Maintenance; Marshal; Menin; Modeling; Molecular; Molecular Biology; Myeloid Leukemia; Myeloproliferative disease; Neoplasms; New Agents; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phosphotransferases; Production; RNA Splicing; Research; Research Personnel; Research Project Grants; Research Support; Resistance; Resources; SYK gene; Sampling; Scientist; Talents; Testing; Therapeutic; Therapeutic antibodies; Translational Research; Translations; Treatment Efficacy; Vaccines; Woman; Work; Xenograft procedure; base; career; career development; chemotherapy; clinical development; clinical efficacy; design; genetic analysis; improved; improved outcome; inhibitor/antagonist; innovation; interest; leukemic stem cell; molecular diagnostics; mouse model; mutant; new therapeutic target; novel; novel therapeutics; pre-clinical; preclinical efficacy; preclinical study; programs; small molecule therapeutics; synergism; therapeutic development; translational physician

Overall Abstract The overall goal of this SPORE in Myeloid Malignancies is to take advantage of our increased understanding of the genetic and molecular basis of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) to develop novel, effective therapeutic strategies for patients with these treatment-resistant neoplasms. The extensive scientific and clinical resources at the Dana-Farber/Harvard Cancer Center (DF/HCC) will be leveraged – marshaling local expertise in cell and molecular biology, genetics, immunology, biostatistics, chemistry, murine models, and clinical trial development – in order to perform innovative pre-clinical studies, to validate novel drug targets in patient cells, and to design and implement clinical trials that will eventually lead to improved outcomes for patients with myeloid malignancies. Each of the four Projects will promote detailed analysis of a promising new target by a combination of pre-clinical studies to optimize therapeutic development and early-stage clinical trials. Project 1 leverages recent exciting data from the laboratory of Dr. Scott Armstrong regarding the efficacy of targeting the MLL-menin interaction, which is essential for maintaining HOXA expression and maintenance of leukemia stem cells. Project 2 is based on the discovery by the Stegmaier laboratory that many cases of AML are dependent on SYK kinase activation, and that SYK activation causes chemotherapy resistance. Project 3 will examine the pre-clinical and clinical efficacy of a novel SF3B1 inhibitor, using an Sf3b1-mutant model developed by the Ebert laboratory, for the treatment MDS. Project 4 will examine the potential synergy of a highly effective vaccine with a potent immunologic checkpoint inhibitor for the treatment of AML. The Cores have been designed to support all projects in translational research. The laboratory and clinical research components of each project will interface with Core 1 for statistical guidance in both experimental design and the interpretation of results. Core 2 will provide biospecimens banking for the samples produced by all projects in the course of clinical trials; these samples will be used for the generation of primagrafts in immunodeficient mice. Samples from the biospecimens bank as well as xenograft samples will, in turn, be available for use by the PI's of all projects. Core 3 will work with the clinical trials in each project for correlative studies. Ultimately, the proposed studies promise to improve the therapy of chemotherapy-resistant AML and splicing factor-mutant MDS, as well as developing an improved immunotherapeutic strategy for AML.

总体抽象 该孢子在髓样恶性肿瘤中的总体目标是利用我们的理解 急性髓样白血病（AML）和骨髓增生综合征（MDS）的遗传和分子基础 为这些耐药性肿瘤患者制定新颖的有效治疗策略。 Dana-Farber/Harvard癌症中心（DF/HCC）的广泛科学和临床资源将是 杠杆率 - 在细胞和分子生物学，遗传学，免疫学，生物统计学，生物学，生物学，生物统计学方面提高本地专业知识 化学，鼠模型和临床试验开发 - 为了进行创新的临床前研究， 验证患者细胞中新型药物靶标，并设计和实施临床试验，最终将导致 骨髓恶霉菌患者的预后改善。四个项目中的每一个都会促进详细的 通过临床前研究的结合来优化治疗性开发，对承诺新目标进行分析 和早期临床试验。项目1利用斯科特博士实验室的最新令人兴奋的数据 关于靶向MLL元素相互作用的效率的阿姆斯特朗，这对于维持 HOXA表达和维持白血病干细胞。项目2基于发现 Stegmaier实验室，许多AML病例取决于SYK激酶的激活，并且SYK 激活会引起化学疗法抗性。项目3将检查A的临床前和临床效率 使用Ebert实验室开发的SF3B1突变模型的新型SF3B1抑制剂用于治疗MDS。 项目4将检查具有潜在免疫学检查点的高效疫苗的潜在协同作用 治疗AML的抑制剂。核心旨在支持翻译中的所有项目 研究。每个项目的实验室和临床研究组件将与Core 1接口 实验设计和结果解释的统计指导。核心2将提供 在临床试验过程中，所有项目生产的样品生产的生物测量银行；这些样本 将用于免疫缺陷小鼠中的发pragrafts。来自生物测量银行的样品 以及异种移植样品又将被所有项目的PI使用。核心3将与 每个项目的临床试验进行纠正研究。最终，拟议的研究有望改善 耐化疗的AML和剪接因子突变MD的治疗，以及开发 改进了AML的免疫治疗策略。