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

基本信息

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
项目类别：
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

项目摘要

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 SPORE 续签申请建立在上一个资助期取得的进展的基础上，这有助于改变白血病护理标准。它重点关注四种重要的新颖机制策略，如果成功，将建立白血病治疗的新标准：表观遗传疗法；使用新型单克隆抗体Hu-8F4进行免疫治疗；通过 MDM2 抑制进行非基因毒性 p53 调节；并改进了 FLT3 ITD 阳性 AML 的 FLT3 抑制剂疗法/组合。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识别可操作的靶点来发现/增强这些新疗法。我们提出了四个由三个核心支持的完全转化研究项目（实验室到临床和返回）。总体具体目标包括： 1) 优化和提高 AIVIL 表观遗传疗法的疗效（项目 1）。该研究领域由项目 1 联合领导者在过去 10 年中开发，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以及基于机制的新型地西他滨组合治疗 AML 的临床试验。 2) 探索新型靶向免疫疗法的抗白血病作用（项目2）。之前通过 SPORE 进行的工作导致了 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对 PR1 构象表位具有特异性的人源化 T 细胞受体样抗体 (8F4)，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 能力。功效。 3) 探索通过抑制 AIVIL 中的 MDIUI2 来增强非基因毒性 p53 激活的策略（项目 3）。之前的工作介绍了针对白血病的 p53 靶向治疗，并取得了有希望的结果。研究人员现在将利用新型 MDM2 抑制剂及其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) 研究最佳使用第三代FLT3抑制剂的联合治疗策略（项目4）。 SPORE 研究人员一直致力于开发用于治疗 AML 的 FLT3 抑制剂，他们现在提议研究更有效的 FLT3 抑制剂作为单一疗法和联合疗法，并研究 crenolanib，这是一种针对最近出现的耐药 FLT3 点突变的 FLT3 抑制剂。