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年的项目中，我们在这方面取得了重大进展，包括在细胞培养和小鼠白血病模型中表征人类白血病中的突变FLT 3等位基因，开发和测试小分子酪氨酸激酶抑制剂作为治疗药物，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，根据最近的发现和项目成员的发现，将我们的努力扩大到新的治疗场所。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FLT 3抑制剂的疗效，通过评估FLT 3抑制剂的临床耐药机制，并开始努力开发JAK 2 V617 F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。Gilliland博士将专注于项目2，了解FLT 3-ITD和FLT 3激活环突变对骨髓和淋巴白血病发病机制的相对贡献，分别使用这些FLT 3突变体的敲入等位基因。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（如PML-RARa，C/EBPa，MLL和AML 1-ETO）的合作，并开发精确的JAK 2 V617 F MPD小鼠模型，用于测试项目1中开发的抑制剂。在项目3中，Tenen博士将继续努力更好地了解突变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。Armstrong博士是该项目的新成员，他将研究MLL融合基因在白血病发生中的作用，单独和与C/EBPa突变合作，基于最近的数据表明这些等位基因合作，并将进一步表征MLL-AF 4和MLL-AF 9介导的白血病小鼠模型中的白血病干细胞。Stone博士将继续领导项目5中该项目的临床转化部分，并将首先专注于在诱导化疗治疗AML的“前期”试验中继续开发FLT 3抑制剂，并在其他项目中开发和验证新疗法，包括例如用于治疗MPD的JAK 2抑制剂。 这些项目将分别得到杰罗姆·里兹博士运行的组织建库和流式细胞术核心B的支持，以及与Donna Neuberg博士运行的生物统计核心C在人类和小鼠模型系统临床试验设计的各个方面的密切互动。总的来说，该计划将建立在以前的优势和开发新疗法的成功记录的基础上，这些新疗法始于靶基因发现，转化的临床前模型的开发，分子靶向疗法的开发和测试，以及I期和II期试验的临床实施。

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.