SPORE University of Texas M.D. Anderson Cancer Center SPORE-Leukemia

SPORE 德克萨斯大学 M.D. 安德森癌症中心 SPORE-白血病

• 批准号: 8918439
• 负责人: HAGOP KANTARJIAN
• 金额: $ 218.37万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918439
• 关键词: Acute Myelocytic Leukemia; Affect; Antibodies; Area; Back; Caring; Cause of Death; Cessation of life; Chronic Myelomonocytic Leukemia; Clinic; Clinical Research; Collaborations; Combined Modality Therapy; Conduct Clinical Trials; Data; Decitabine; Development; Disease; Drug resistance; Dysmyelopoietic Syndromes; Elderly; Epigenetic Process; Epitopes; FLT3 gene; FLT3 inhibitor; Functional disorder; Funding; Generations; Genomics; Goals; Hematologic Neoplasms; Hematopoietic; Immunotherapy; In Vitro; Individual; Knowledge; Laboratories; MDM2 gene; Mentors; Methods; Modality; Monoclonal Antibodies; Myeloproliferative disease; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Point Mutation; Publications; Records; Research; Research Personnel; Research Project Grants; Science; Specificity; T-Cell Receptor; Testing; Therapeutic; Therapy Clinical Trials; Toxic effect; Translating; Translational Research; Treatment Protocols; University of Texas M D Anderson Cancer Center; Vaccines; Work; base; career development; chemotherapy; drug development; exportin 1 protein; improved; in vivo; inhibitor/antagonist; leukemia; next generation; novel; novel strategies; novel therapeutic intervention; outcome forecast; phase II trial; pre-clinical; preclinical study; programs; standard of care; targeted treatment; therapy resistant

DESCRIPTION (provided by applicant): Leukemias affect about 60,000 individuals, and cause the death of 23,000 individuals annually in the US. The Leukemia SPORE renewal application builds upon progress achieved in the previous funding period, which contributed to a change in standards of care in leukemia. It focuses on four important novel mechanistic strategies which if successful, will establish new standards of therapies in leukemia: epigenetic therapy; immunotherapy with a new monoclonal antibody Hu-8F4; non-genotoxic p53 modulation by MDM2 inhibition; and improved FLT3 inhibitors therapies/ combinations in FLT3 ITD positive AML. Our overall goal is to discover/enhance these new therapies through better understanding of the causal pathophysiologies in leukemia and the identification of actionable targets. We propose four fully translational research projects (laboratory to clinic and back) supported by three cores. The overall Specific Aims include: 1) To optimize and improve the efficacy of epigenetic therapies in AIVIL (Project 1). This research area was developed by Project 1 co-leaders over the past 10 years, and resulted in the FDA approval of decitabine as an epigenetic therapy for MDS. The new aims investigate new targeted approaches to epigenetic therapy and clinical trials of novel, mechanism-based decitabine combinations in AML. 2) To explore anti-leukemic effects of a novel targeted immune therapy (Project 2). Previous work through this SPORE resulted in the development of the PRI vaccine. Project investigators will now test a newly discovered humanized T cell receptor-like antibody (8F4) with specificity for a conformational epitope of PR1 in vitro and in vivo, and conduct a phase 1 clinical trial of this novel monoclonal antibody to determine its anti- AML efficacy. 3) To explore strategies to enhance non-genotoxic p53 activation by MDIUI2 inhibition in AIVIL (Project 3). Previous work introduced p53-targeted therapy in leukemia with promising results. Investigators will now extend these findings using preclinical and clinical studies of novel MDM2 inhibitors and combinations, and further develop p53-targeted therapies of the leukemia microenvironment. 4) To investigate combined modality therapeutic strategies forthe optimal use of 3rd generation FLT3 inhibitors (Project 4). SPORE investigators have championed the development of FLT3 inhibitors in AML, they now propose to study more potent FLT3 inhibitors as monotherapy and in combinations, as well as study crenolanib, a FLT3 inhibitor active against recently emerging and drug-resistant FLT3 point mutations.

描述（由申请人提供）：在美国，白血病每年影响约60,000人，并导致23,000人死亡。白血病孢子更新申请建立在前一个资助期取得的进展基础上，这有助于改变白血病的护理标准。它着重于四种重要的新的机制策略，如果成功，将建立白血病治疗的新标准：表观遗传治疗；新单克隆抗体Hu-8F4的免疫治疗；MDM2抑制非基因毒性p53；改善FLT3抑制剂治疗/联合治疗FLT3 ITD阳性AML。我们的总体目标是通过更好地了解白血病的因果病理生理学和确定可操作的靶点来发现/增强这些新疗法。我们提出了四个完全转化的研究项目（从实验室到临床和返回），由三个核心支持。总体具体目标包括：1)优化和提高表观遗传治疗AIVIL的疗效（项目1）。这个研究领域是由Project 1的共同领导在过去的10年里发展起来的，并导致FDA批准地西他滨作为MDS的表观遗传疗法。新的目标是研究表观遗传治疗的新靶向方法和新型的、基于机制的地西他滨联合治疗AML的临床试验。2)探索一种新型靶向免疫疗法的抗白血病作用（项目2）。先前通过该孢子进行的工作导致PRI疫苗的开发。项目研究人员现在将在体外和体内测试一种新发现的人源化T细胞受体样抗体（8F4），该抗体具有PR1构象表位的特异性，并对这种新型单克隆抗体进行1期临床试验，以确定其抗AML的功效。3)探索通过抑制MDIUI2增强AIVIL非基因毒性p53激活的策略（项目3）。先前的研究介绍了p53靶向治疗白血病的方法，并取得了令人鼓舞的结果。研究人员现在将利用新的MDM2抑制剂和组合的临床前和临床研究来扩展这些发现，并进一步开发针对白血病微环境的p53靶向疗法。4)研究第三代FLT3抑制剂的最佳使用联合治疗策略（项目4）。SPORE研究人员支持在AML中开发FLT3抑制剂，他们现在建议研究更有效的FLT3抑制剂作为单一疗法和联合疗法，以及研究crenolanib（一种FLT3抑制剂，对最近出现的耐药FLT3点突变有活性）。