The Therapy of CML

该计划项目资助的重点是基于其分子病理生理学及其对生物疗法，同种异体移植和免疫方法的独特易感性，开发新型，有效的CML疗法。该项目在过去19年中一直获得持续资助，成效显著。该计划在竞争性更新中重新组织了2个新项目，以解决该领域的主要问题和治疗机会。这是一个由6个项目和5个核心组成的高度整合的项目，形成了一个全面的转化研究项目，研究范围涵盖CML的基础生物学和人类临床试验。本修订申请进行了广泛的修订，以解决审查的批评。A1应用程序中的项目3将被删除，项目将重新编号。项目1和2涉及临床研究，将项目的科学进展转化为旨在提高CML分子完全缓解率和无病生存率的人体临床试验。项目1研究评估酪氨酸激酶抑制剂的化学生物疗法、抗原特异性免疫疗法和旨在克服伊马替尼耐药性的低甲基化疗法。项目2涉及造血移植的新策略，重点是增强移植物抗白血病和针对PR 1的抗原特异性细胞免疫治疗，移植后低甲基化治疗和通过干扰SDF-1和CXCR 4的相互作用来提高治疗指数的化学增敏。.项目3研究微环境和CML的相互作用，以及干扰这些相互作用的潜在治疗干预措施。项目4评估了CML干细胞对酪氨酸激酶抑制剂耐药的机制以及规避耐药的潜在治疗干预措施。项目5研究bcr-abl肿瘤发生的分子机制分泌细胞死亡因子、脂质运载蛋白和通过Jak-2的信号传导。项目6检查CML的表观基因组，包括选定表观遗传标记的预测和预后测试以及接受低甲基化治疗的患者的表观遗传参数的药效学分析。包括五个核心：核心A是行政核心。核心B是生物统计学。核心C提供细胞培养和克隆形成测定。核心D是细胞收集和分配核心。核心E是GMP细胞实验室和免疫评估核心，用于人体临床试验的细胞处理和这些研究和研究项目所需的免疫评估。这是一个高效、高度集成的CML新型疗法开发计划。

This Program Project Grant focuses on development of novel, effective therapies for CML, based upon its molecular pathophysiology and its unique susceptibility to biologic therapies, allotransplantation and immunotherapeutic approaches. This program has been highly productive, with continuous funding for the last 19 years. The program is reorganized with 2 new projects in the competitive renewal to address the major issues and therapeutic opportunities in this field. This is a highly integrated program of 6 projects and 5 cores are proposed forming a comprehensive translational research program with investigation spanning the basic biology of CML to human clinical trials. This amended application is extensively revised to address the critique of the review. Project 3 from the A1 application is deleted and the projects are renumbered. Projects 1 and 2 involve clinical investigations translating scientific advances from the projects into human clinical trials designed to increase the rate of molecular complete remission and disease free survival in CML. Project 1 studies chemo-biologic therapies assessing tyrosine kinase inhibitors, antigen specific immunotherapy and hypomethylating therapy designed to overcome imatinib resistance. Project 2 involves novel strategies for hematopoietic transplantation focusing on enhancement of graft-vs-leukemia and antigen specific cellular immunotherapy against PR1, post transplant hypomethylating therapy and chemosensitization by interference with interaction of SDF-1 and CXCR4 to improve the therapeutic index. . Project 3 examines the interaction ofthe microenvironment and CML, and potential therapeutic interventions to interfere with these interactions. Project 4 evaluates the mechanisms of resistance to tyrosine kinase inhibitors in CML stem cells and potential therapeutic interventions to circumvent resistance. Project 5 examines molecular mechanisms of bcr-abl oncogenesis secreted cell death factors, lipocalins, and signaling through Jak-2. Project 6 examines the epigenome in CML, including Predictive and prognostic testing of selected epigenetic markers and pharmacodynamic analysis of epigenetic parameters in patients treated with hypomethylating therapies. Five cores are included: Core A is the administrative core. Core B is biostatistics. Core C provides cell culture and clonogenic assays. Core D is the cell collection and distribution core. Core E is the GMP Cell Laboratory and Immune Assessment Core, required for cell processing for human clinical trials and immune assessments required for these studies and the research projects. This is a productive, highly integrated program for development of novel therapies for CML.