Targeted Therapy for Leukemia

 描述(由申请人提供)：伯德翻译实验室研究计划专注于基础和翻译生物学问题，以开发针对恶性血液病的新的免疫学和靶向治疗。慢性淋巴细胞白血病(CLL)被用作我们的疾病模型，因为它允许将自发性白血病小鼠模型中的机制和遗传学研究与使用原始肿瘤样本的研究相结合，从而增强了我们研究结果的临床相关性。我们高度协作的实验室团队致力于识别、剖析和解决白血病治疗开发中的挑战，利用各自的优势推动项目进入临床应用。它还使我们能够利用不同的技术(例如蛋白质组学、下一代测序)，并进入新的领域(例如新的药物输送方法、靶标识别、引入新的动物模型)，以将我们的发现转化为人类多种疾病。这一战略导致了强大的合作，从其他领域招募了熟练的研究人员，将他们的知识应用于白血病。我设想我的研究的最大影响将来自于将针对肿瘤生存途径的治疗方法与逆转免疫耐受以促进长期缓解或治愈的药物相结合。到目前为止，我的工作已经批准了两种用于延长生存的CLL疗法的代理。我们正在进行的关于imbrutinib的工作消除了一种普遍持有的范式，即当不存在特定的遗传异常时，不可能开发出一般的“疾病靶向治疗”。我的假设是，一般的疾病靶向治疗需要肿瘤靶向和免疫双重调节。我寻求积极发展这一概念，并根据我们的数据将其扩展到其他领域。

 DESCRIPTION (provided by applicant): The Byrd translational laboratory research program focuses on basic and translational biologic questions to develop novel immunologic and targeted therapies for hematologic malignancies. Chronic lymphocytic leukemia (CLL) is utilized as our disease model as it allows integration of mechanistic and genetic studies in spontaneous leukemia mouse models with studies using primary tumor samples, thereby enhancing the clinical relevance of our findings. Our highly collaborative laboratory team works to identify, dissect, and solve challenges in leukemia therapeutic development that capitalizes on the strengths of each to drive projects to clinical application. It also allows us to exploit diverse techniques (e.g. proteomics, next-generation sequencing) and embark on new areas (e.g. novel drug delivery methods, target identification, introduction of new animal models) to translate our findings across multiple human diseases. This strategy has resulted in powerful collaborations, recruiting skilled researchers from other fields to apply their knowledge to leukemia. I envision the greatest impact from my research will come from integrating therapeutics that target tumor survival pathways with agents that reverse immune tolerance to facilitate long-term remissions or cure. My work to date has resulted in the approval of two agents for CLL therapy that prolong survival. Our ongoing work with imbrutinib dispels a commonly held paradigm that it is not possible to develop a general "disease-targeted therapy" when a specific genetic aberration is not present. My hypothesis is that general disease-targeted therapy requires dual tumor-targeted and immunologic modulation. I seek to aggressively develop this concept and extend it to other areas as our data directs us.