SPORE in Myeloid Malignancies

总体摘要 在恶性髓系中这个孢子的总体目标是利用我们不断增长的理解 急性髓系白血病(AML)和骨髓增生异常综合征(MDS)的遗传和分子基础 为这些耐药肿瘤患者开发新的、有效的治疗策略。这个 达纳-法伯/哈佛癌症中心(DF/HCC)的广泛科学和临床资源将是 利用当地在细胞和分子生物学、遗传学、免疫学、生物统计学、 化学、小鼠模型和临床试验开发--为了进行创新的临床前研究， 在患者细胞中验证新的药物靶点，并设计和实施最终将导致 改善了髓系恶性肿瘤患者的预后。四个项目中的每个项目都将促进详细的 结合临床前研究分析一个有前景的新靶点以优化治疗开发 以及早期临床试验。项目1利用了斯科特博士实验室最新的令人兴奋的数据 阿姆斯特朗关于靶向MLL-薄荷素相互作用的有效性，这对维持 Hoxa基因在白血病干细胞中的表达和维持。项目2是基于 Stegmaier实验室认为，许多AML病例依赖于SYK激酶激活，而SYK 激活会导致化疗耐药。项目3将检查临床前和临床疗效 使用Ebert实验室开发的SF3B1突变模型治疗MDS的新型SF3B1抑制剂。 项目4将研究一种具有强大免疫检查点的高效疫苗的潜在协同作用 治疗急性髓系白血病的抑制剂。这些核心已设计为支持所有项目的翻译 研究。每个项目的实验室和临床研究部分将与核心1对接，以便 在实验设计和结果解释方面的统计指导。核心2将提供 所有项目在临床试验过程中产生的样本的生物谱库；这些样本 将用于在免疫缺陷小鼠身上产生原始移植物。来自生物质库的样本 以及异种移植样本，反过来将可供所有项目的PI使用。酷睿3将与 对每个项目的临床试验进行相关研究。最终，拟议的研究有望改善 耐药AML和剪接因子突变型MDS的治疗及其进展 改进了急性髓系白血病的免疫治疗策略。

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.