Development of Novel Therapeutic Strategies in Human Leukemias

描述（由申请人提供）：该项目的总体目标是了解人类白血病的遗传基础，并在此基础上开发新的治疗方法。在过去9年的项目中，我们在这方面取得了重大进展，包括在人类白血病细胞培养和小鼠白血病模型中突变FLT3等位基因的表征，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推进I期和II期临床试验。在接下来的5年研究期间，我们将在这些成功的基础上继续努力，并根据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Project 1中，Dr. Griffin将专注于通过“联合靶向治疗”来提高FLT3抑制剂的疗效，通过评估FLT3抑制剂的临床耐药机制，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殖性疾病的治疗剂。Gilliland博士将在项目2中重点了解FLT3- itd和FLT3激活环突变对髓系和淋巴系白血病发病机制的相对贡献，分别使用这些FLT3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（如PML-RARa， C/EBPa， MLL和AML1-ETO）的合作，并开发准确的小鼠JAK2V617F MPD模型，用于测试项目1中开发的抑制剂。在Project 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，将研究MLL融合基因在白血病发生中的作用，单独或与C/EBPa突变合作，基于最近的数据表明这些等位基因相互合作，并将进一步表征MLL- af4和MLL- af9介导的白血病小鼠模型中的白血病干细胞。Stone博士将继续在项目5中领导该项目的临床转化部分，并将最初专注于在诱导化疗治疗AML的“前期”试验中继续开发FLT3抑制剂，并实施在其他项目中开发和验证的新疗法，例如用于治疗MPD的JAK2抑制剂。这些项目将分别由Jerome Ritz博士负责的组织银行和流式细胞术核心B，以及Donna Neuberg博士负责的生物统计学核心C在人类和小鼠模型系统临床试验设计的各个方面进行密切互动。总的来说，该项目将建立在先前的优势和在开发新疗法方面的成功记录的基础上，从目标基因的发现、临床前转化模型的开发、分子靶向疗法的开发和测试，以及I期和II期临床试验的实施开始。

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.