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

描述(申请人提供)：白血病影响约60,000人，在美国每年导致23,000人死亡。白血病孢子更新申请建立在前一个供资期间取得的进展的基础上，这有助于改变白血病的护理标准。它侧重于四种重要的新机制策略，如果成功，将建立白血病治疗的新标准：表观遗传治疗；新的单抗Hu-8F4的免疫治疗；通过抑制MDM2来调节非遗传毒性的p53；以及改进的Flt3抑制剂治疗/组合治疗Flt3 ITD阳性AML。我们的总体目标是通过更好地了解白血病的病因病理生理学和确定可操作的靶点来发现/加强这些新的治疗方法。我们提出了四个完全转换的研究项目(实验室到临床和回来)，由三个核心支持。总的具体目标包括：1)优化和提高AIVIL表观遗传疗法的疗效(项目1)。这一研究领域是由项目1的共同领导者在过去10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。新的目标是研究表观遗传治疗的新的有针对性的方法，以及急性髓细胞白血病新的、基于机制的地西他滨联合的临床试验。2)探索一种新型靶向免疫疗法的抗白血病作用(项目2)。之前通过这种孢子进行的工作导致了PRI疫苗的开发。项目研究人员现在将在体内外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，并对这种新型单抗进行一期临床试验，以确定其抗AML的效果。3)探索通过抑制AIVIL中MDIUI2来增强非遗传毒性P53激活的策略(项目3)。以前的工作介绍了白血病的P53靶向治疗，结果令人振奋。研究人员现在将通过对新型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)研究最佳使用第三代Flt3抑制剂的联合治疗策略(项目4)。孢子研究人员一直支持在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治疗，以及研究crenolanib，一种有效对抗最近出现的和耐药的Flt3点突变的Flt3抑制剂。

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.