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：
8734325
负责人：
HAGOP KANTARJIAN
金额：
$ 216.14万
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734325
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 pre-clinical preclinical study programs standard of care 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）：白血病影响约60,000人，并在美国每年导致23,000人死亡。白血病孢子的更新申请基于上一个融资期的进展，这导致白血病标准的变化。它着重于四种重要的新型机械策略，如果成功，将建立白血病的新疗法标准：表观遗传疗法；新单克隆抗体HU-8F4的免疫疗法；通过MDM2抑制，非生物毒性p53调节；并改善了FLT3 ITD阳性AML中的FLT3抑制剂疗法/组合。我们的总体目标是通过更好地理解白血病的因果病理生理和可行靶标的鉴定，从而发现/增强这些新疗法。我们建议由三个核心支持的四个完全转化的研究项目（诊所和背部实验室）。总体具体目的包括：1）优化和提高Aivil表观遗传疗法的功效（项目1）。该研究领域是在过去的10年中由项目1共同领导者开发的，并导致了Decitabine作为MDS的表观遗传疗法的FDA批准。新目标研究了新型基于机制的Decitabine组合的新的靶向遗传疗法和临床试验。 2）探索新型靶向免疫治疗的抗白血病作用（项目2）。以前通过该孢子的工作导致了PRI疫苗的开发。项目研究人员现在将测试新发现的人源性T细胞受体样抗体（8F4），其特异性对于Pr1的体外和体内构象表位，并进行了这种新型单克隆抗体的1期临床试验，以确定其抗AML功效。 3）探索策略以增强AIVIL中MDIUI2抑制的非生物毒性p53激活（项目3）。先前的工作引入了白血病的P53靶向疗法，结果令人鼓舞。现在，研究人员将使用新型MDM2抑制剂和组合的临床前和临床研究扩展这些发现，并进一步发展为白血病微环境的p53靶向疗法。 4）研究以最佳使用第三代FLT3抑制剂的合并方式治疗策略（项目4）。孢子研究人员倡导了AML中FLT3抑制剂的发展，他们现在建议研究更多有效的FLT3抑制剂，例如单一疗法和组合，以及研究Crenolanib，crenolanib是一种活跃的FLT3抑制剂，以针对最近出现的新兴和药物抗药性的FLT3点突变。