Development of Novel Therapeutic Strategies in Human Leukemias

描述(由申请人提供)：该计划的总体目标是了解人类白血病的遗传基础，并基于这些见解开发新的治疗方法。在过去9年的计划中，我们在这方面取得了重大进展，包括在细胞培养和白血病小鼠模型中鉴定人类白血病中突变的Flt3等位基因，开发和测试小分子酪氨酸激酶抑制剂作为治疗剂，并将这些小分子抑制剂带入I期和II期临床试验。在下一个拟议的5年研究期间，我们将在这些成功的基础上再接再厉，并根据计划项目成员的最新发现和发现，将我们的努力扩展到新的治疗场所。在项目1中，Griffin博士将专注于通过使用“联合靶向治疗”来提高Flt3抑制剂的疗效，评估临床对Flt3抑制剂的耐药机制，并开始努力开发JAK2V617F的小分子酪氨酸激酶抑制剂作为骨髓增生性疾病的治疗药物。Gillland博士将在项目2中重点了解Flt3-ITD和Flt3激活环突变在髓系白血病和淋巴细胞性白血病发病机制中的相对作用，使用这些突变的敲入等位基因。他将继续致力于了解这些等位基因与其他白血病相关等位基因的合作，如PML-RARA、C/EBPA、MLL和AML1-ETO，并为项目1中开发的抑制剂开发准确的JAK2V617F MPD小鼠模型。在项目3中，Tenen博士将继续努力更好地了解突变的造血转录因子在白血病发病机制中的作用，包括PML-RARA、C/EBPA和PU.1。阿姆斯特朗博士是该计划的新成员，他将基于最近的数据，研究MLL融合基因在白血病发生中的作用，以及与C/EBPA突变的协同作用，并将在MLL-AF4和MLL-AF9介导的白血病小鼠模型中进一步表征白血病干细胞。斯通博士将在项目5中继续领导该计划的临床翻译部分，最初将重点放在用诱导化疗治疗急性髓细胞白血病的“前期”试验中继续开发Flt3抑制剂，并在其他项目中开发和验证新疗法时实施这些疗法，例如，用于治疗MPD的JAK2抑制剂。这些项目将分别由Jerome Ritz博士运营的组织银行和流式细胞术核心B以及与Donna Neuberg博士运营的生物统计学核心C在人类和小鼠模型系统临床试验设计的所有方面的密切互动提供支持。总体而言，该计划将在开发新疗法的流水线中巩固以前的优势和已证明的成功记录，这些新疗法始于靶基因发现，开发分子靶向疗法的转化、开发和测试的临床前模型，以及在第一阶段和第二阶段试验中的临床实施。

DESCRIPTION (provided by applicant): The overall goal of this program has been to understand the genetic basis of human leukemias, and to develop novel therapeutic approaches based on these insights. During the past 9 years of the program, we have made major strides in this regard, including characterization of mutant FLT3 alleles in human leukemias in cell culture and murine models of leukemia, developing and testing small molecule tyrosine kinase inhibitors as therapeutic agents, and bringing these small molecule inhibitors forward into Phase I and Phase II clinical trials. During the next proposed 5-year study period we will build on these successes, and expand our efforts into new therapeutic venues based on recent findings and discoveries among members of the Program Project. In Project 1, Dr. Griffin will focus on improving the efficacy of FLT3 inhibitors by using "combination targeted therapy", by evaluating the mechanisms of clinical resistance to FLT3 inhibitors, and initiating efforts to develop small molecule tyrosine kinase inhibitors of JAK2V617F as therapeutic agents in the myeloproliferative diseases. Dr. Gilliland will focus in Project 2, on understanding the relative contributions of FLT3-ITD and FLT3 activation loop mutations to the pathogenesis of myeloid and lymphoid leukemias, respectively, using knock-in alleles of these FLT3 mutants. He will focus continued effort on understanding cooperation of these alleles with other leukemia associated alleles, such as PML-RARa, C/EBPa, MLL and AML1-ETO, and in developing accurate murine models of JAK2V617F MPD for testing inhibitors developed in Project 1. In Project 3, Dr. Tenen will continue efforts to better understand the contributions of mutant hematopoietic transcription factors in pathogenesis of leukemia, including PML-RARa, C/EBPa, and PU.1. Dr. Armstrong is a new addition to the Program, and will study the role of MLL fusion genes in leukemogenesis, alone and in cooperation with mutations of C/EBPa based on recent data suggesting that these alleles cooperate, and will further characterize leukemia stem cells in murine models of MLL-AF4 and MLL-AF9 mediated leukemias. Dr. Stone will continue to lead the clinical translational component of this Program in Project 5, and will initially focus on continued development of FLT3 inhibitors in "up-front" trials with induction chemotherapy to treat AML, and to implement novel therapies as they are developed and validated in the other projects, including, for example, JAK2 inhibitors for treatment of MPD. These Projects will each be supported by the Tissue Banking and Flow Cytometry Core B run by Dr. Jerome Ritz, and by close interactions with the Biostatistical Core C run by Dr. Donna Neuberg in all aspects of clinical trial design in human and murine model systems. Collectively, the Program will build on previous strengths and a demonstrated track record of success in the pipeline of developing novel therapies that begins with target gene discovery, development of preclinical models of transformation, development and testing of molecularly targeted therapies, and clinical implementation in Phase I and Phase II trials.