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

整体项目总结 白血病影响着大约6万人，在美国每年导致2.4万人死亡。这个 白血病孢子更新申请是在前几个供资期间取得进展的基础上提出的， 促成了白血病护理标准的几次变化。它提出了五部重要的小说 机械性策略，如果成功，将建立白血病治疗的新标准：表观遗传学 治疗调节；新型单抗Hu-8F4的免疫治疗；非遗传毒性的p53调节 通过抑制MDM2；新的自然杀伤(NK)细胞疗法；靶向氧化磷酸化(OxPhos) 使用新型OxPhos抑制剂的白血病。我们的总体目标是通过 更好地了解白血病的病因病理生理学和识别可操作的靶点。 我们提出了五个完全转化的研究项目(实验室到临床和回来)，由三个核心支持。 总体的具体目标是：1)优化和提高急性髓系白血病表观遗传疗法的疗效 (项目1)。这一研究领域是由项目1的共同领导者在过去14年中开发的，并导致 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) 用于治疗不宜强化化疗的老年急性髓系白血病。新的目标是加强 抑制CDK9的表观遗传效应。2)探讨一种新型靶向药物的抗白血病作用 使用8F4单抗进行免疫治疗(项目2)。先前通过该孢子进行的工作导致了 在PR1疫苗的开发和新发现的人源化T细胞受体样蛋白的发现方面 体内外对PR1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 在接受治疗的患者中，了解其成功/失败的机制。3)探索策略 通过抑制MDM2增强急性髓系白血病非遗传毒性P53的激活(项目3)。以前的工作 在白血病中引入了p53靶向治疗，前景看好。调查人员现在将使用以下方法扩展这些发现 新型MDM2抑制剂及其与细胞凋亡诱导剂联合应用的临床前和临床研究 (Ventoclax)。4)研究白血病的NK-CAR细胞治疗(项目4)。这是一家内部办公室 通过白血病孢子CEP资助的治疗策略，显示出有希望的转化性治疗 价值。5)开发基于OxPhos的白血病靶向治疗(项目5)。这是另一家内部公司 以前由白血病孢子支持的研究人员研究的新方法和分子 DRP，并根据其有希望的结果扩展为一个完整的项目。

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.