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

SPORE 德克萨斯大学 MD 安德森癌症中心 - 白血病

• 批准号: 10247497
• 负责人: Marina Y Konopleva
• 金额: $ 168.98万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247497
• 关键词: Acute Myelocytic Leukemia; Address; Adoptive Transfer; Affect; Antibodies; Antigens; Apoptosis; Area; Autologous; BCL2 gene; Back; Biological; Biological Response Modifier Therapy; CD19 gene; CDK9 Protein Kinase; Cancer Center; Caring; Cause of Death; Cell Survival; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Cross Presentation; Data; Decitabine; Dependence; Development; Diagnosis; Doctor of Medicine; Dominant-Negative Mutation; Dose; Elderly Acute Myeloblastic Leukemia; Engineering; Epigenetic Process; Epitopes; European; FLT3 gene; FLT3 inhibitor; Failure; Functional disorder; Funding; Genomics; Goals; HLA-A2 Antigen; Immune Targeting; Immunotherapy; In Vitro; Individual; Interleukin-15; Laboratories; Lead; Logistics; MDM2 gene; Malignant Neoplasms; Mediating; Mentors; Metabolism; Modality; Molecular Conformation; Monoclonal Antibodies; Mutate; Myeloproliferative disease; NK cell therapy; Natural Killer Cells; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Prognosis; RUNX1 gene; RUNX3 gene; Refractory; Regimen; Relapse; Research; Research Personnel; Research Project Grants; Residual state; Resistance; Science; Signal Transduction; Specificity; T-Cell Receptor; T-Lymphocyte; TP53 gene; Texas; Therapeutic; Transforming Growth Factor beta; Translating; Translational Research; Umbilical Cord Blood; Universities; Work; alternative treatment; base; career; chemotherapy; combinatorial; design; drug development; effective therapy; efficacy testing; epigenetic silencing; epigenetic therapy; first-in-human; genetic manipulation; improved; in vivo; inhibitor/antagonist; leukemia; leukemia treatment; leukemic stem cell; molecular subtypes; next generation; novel; novel therapeutics; phase 1 study; phase I trial; pre-clinical; preclinical study; programs; side effect; success; targeted treatment; vaccine discovery

OVERALL PROJECT SUMMARY Leukemias affect about 60,000 individuals, and cause the death of 24,000 individuals annually in the US. The Leukemia SPORE renewal application builds upon progress achieved in the previous funding periods, which contributed to several changes in the standards of care in leukemia. It proposes five important novel mechanistic strategies which if successful, will establish new standards of therapies in leukemia: epigenetic therapy modulation; immunotherapy with a new monoclonal antibody Hu-8F4; non-genotoxic p53 modulation by MDM2 inhibition; novel natural-killer (NK) cellular therapy; targeting oxidative phosphorylation ( OxPhos) in leukemia with novel OxPhos inhibitors. Our overall goal is to discover/enhance these new therapies through a better understanding of the causal pathophysiologies in leukemia and the identification of actionable targets. We propose five fully translational research projects (laboratory to clinic and back) supported by three cores. The overall Specific Aims are: 1) Optimize and improve the efficacy of epigenetic therapies in AML (Project 1). This research area was developed by Project 1 co-leaders over the past 14 years, and resulted in the FDA approval of decitabine as an epigenetic therapy for MDS, and the European EMEA approval (2012) for the treatment of elderly AML unfit for intensive chemotherapy. The new aims investigate enhancing the epigenetic effects through suppression of CDK9. 2) Explore anti-leukemic effects of a novel targeted immune therapy using 8F4 monoclonal antibody (Project 2). Previous work through this SPORE resulted in the development of the PR1 vaccine and the discovery of a newly discovered humanized T cell receptor-like antibody (8F4) with specificity for a conformational epitope of PR1 in vitro and in vivo. . Project investigators will now test the efficacy of the new 8F4 antibody and conduct a phase I clinical trial to determine its anti- AML efficacy, and understand the mechanisms behind its success/failure in patients treated. 3) Explore strategies to enhance non-genotoxic p53 activation by MDM2 inhibition in AML (Project 3). Previous work introduced p53-targeted therapy in leukemia as promising. Investigators will now extend these findings using preclinical and clinical studies of novel MDM2 inhibitors and combinations with apoptosis inducing agents (venetoclax). 4) Investigate NK-CAR cellular therapy in leukemia (Project 4). This is an in-house therapeutic strategy funded through a Leukemia SPORE CEP and showing promising translational therapeutic value. 5) Develop OxPhos- based targeted therapies in leukemia (Project 5). This is another in-house developed approach and molecule investigated by investigators previously supported by a Leukemia SPORE DRP, and expanded into a full project based on its promising results.

总体项目摘要 在美国，白血病影响约60，000人，并且每年导致24，000人死亡。的 白血病SPORE续签申请建立在之前资助期取得的进展的基础上，其中 促成了白血病护理标准的几项变化。它提出了五个重要的小说 机制策略，如果成功，将建立白血病治疗的新标准：表观遗传 治疗调节;新单克隆抗体Hu-8F4免疫治疗;非遗传毒性p53调节 通过MDM2抑制;新型自然杀伤（NK）细胞疗法;靶向氧化磷酸化（OxPhos）， 新型OxPhos抑制剂治疗白血病。我们的总体目标是通过一个 更好地理解白血病的病因病理生理学和确定可采取行动的目标。 我们提出了五个完全转化的研究项目（实验室到临床和背部）由三个核心支持。 总体具体目标是：1）优化和提高AML表观遗传疗法的疗效 （项目1）。这个研究领域是由项目1共同领导人在过去14年中开发的，并导致了 FDA批准地西他滨作为MDS的表观遗传疗法，以及欧洲EMEA批准（2012年） 用于治疗不适合强化化疗的老年AML。新的目标是提高 通过抑制CDK9的表观遗传效应。2)探索新型靶向药物的抗白血病作用 使用8F4单克隆抗体的免疫治疗（项目2）。以前通过此SPORE进行的工作导致 在PR1疫苗的开发和新发现的人源化T细胞受体样 在体外和体内对PR 1的构象表位具有特异性的抗体（8F4）。.项目调查员 现在将测试新的8F4抗体的疗效，并进行I期临床试验，以确定其抗AML 有效性，并了解其在治疗患者中成功/失败背后的机制。3)探索战略 在AML中通过MDM2抑制增强非遗传毒性p53激活（项目3）。以前的工作 介绍了p53靶向治疗白血病的前景。调查人员现在将使用 新的MDM2抑制剂及其与凋亡诱导剂的组合的临床前和临床研究 （venetoclax）. 4)研究白血病中的NK-CAR细胞疗法（项目4）。这是一个内部 通过白血病孢子CEP资助的治疗策略，并显示出有前途的转化治疗 值5)开发基于OxPhos的白血病靶向治疗（项目5）。这是另一个内部 开发的方法和分子研究的研究人员先前支持的白血病孢子 DRP，并根据其有希望的结果扩展为一个完整的项目。