Targeted Therapy for Leukemia

白血病靶向治疗

• 批准号: 10251287
• 负责人: JOHN C. BYRD
• 金额: $ 97.12万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251287
• 关键词: Animal Model; Area; Biological; Chronic Lymphocytic Leukemia; Collaborations; Data; Disease; Disease model; Disease remission; Drug Delivery Systems; Genetic; Genetic study; Hematologic Neoplasms; Hematopoietic Neoplasms; Immune Tolerance; Immunotherapy; Investigation; Knowledge; Laboratories; Laboratory Research; Methods; Pathway interactions; Patients; Primary Neoplasm; Proteomics; Research; Research Personnel; Sampling; Techniques; Translating; Work; adult leukemia; clinical application; clinically relevant; curative treatments; human disease; immunoregulation; leukemia; mouse model; next generation sequencing; novel; novel therapeutics; programs; public health relevance; recruit; targeted treatment; therapeutic development; therapeutic target; tumor

 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.

 描述（由申请人提供）：Byrd 转化实验室研究计划专注于基础和转化生物学问题，以开发针对血液恶性肿瘤的新型免疫学和靶向疗法，因为它允许将机械性和慢性淋巴细胞性白血病（CLL）整合为我们的疾病模型。自发性白血病小鼠模型的遗传学研究以及使用原发性肿瘤样本的研究，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、剖析和解决挑战。白血病治疗的发展利用各自的优势来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）并着手新的领域（例如新的药物方法、靶点识别、引入新的药物方法）。新的动物模型）将我们的发现转化为多种人类疾病。这一策略带来了强有力的合作，招募了来自其他领域的研究人员将他们的知识应用于白血病。我预计我的研究的最大影响将来自于针对肿瘤的整合疗法。迄今为止，我的工作已经批准了两种可延长生存期的 CLL 治疗药物，这消除了一种普遍认为的范例。当不存在特定的遗传畸变时，有可能开发出通用的“疾病靶向疗法”。我的假设是，通用的疾病靶向疗法需要肿瘤靶向和免疫调节的双重作用，我寻求积极发展这一概念并将其扩展到其他领域。我们的数据指导我们的领域。

项目成果

Venetoclax Adds a New Arrow Targeting Relapsed CLL to the Quiver.

Venetoclax 向 Quiver 中添加了针对复发 CLL 的新箭头。

• 发表时间: 2016-01-11
• 影响因子: 50.3
• 作者: Rogers, Kerry A;Byrd, John C
• 通讯作者: Byrd, John C

Entospletinib in Combination with Induction Chemotherapy in Previously Untreated Acute Myeloid Leukemia: Response and Predictive Significance of HOXA9 and MEIS1 Expression.

Entospletinib 联合诱导化疗治疗既往未经治疗的急性髓系白血病：HOXA9 和 MEIS1 表达的反应和预测意义。

• 发表时间: 2020
• 作者: Walker, Alison R;Byrd, John C;Blachly, James S;Bhatnagar, Bhavana;Mims, Alice S;Orwick, Shelley;Lin, Tara L;Crosswell, Howland E;Zhang, Danjie;Minden, Mark D;Munugalavadla, Veerendra;Long, Lauren;Liu, Jinfeng;Pan, Yang;Oellerich, Thomas;Ser
• 通讯作者: Ser

Novel SF3B1 in-frame deletions result in aberrant RNA splicing in CLL patients.

新型 SF3B1 框内缺失导致 CLL 患者 RNA 剪接异常。

• DOI: 10.1182/bloodadvances.2017007062
• 发表时间: 2017-06-27
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Anant A. Agrawal;M. Seiler;Lindsey T Brinton;Rose Mantel;R. Lapalombella;J. Woyach;A. Johnson;P. Zhu;M. Warmuth;Lihua Yu;J. Byrd;Peter G. Smith;J. Blachly;S. Buonamici
• 通讯作者: S. Buonamici

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.

Acalabrutinib (ACP-196) 治疗复发性慢性淋巴细胞白血病。

• DOI: 10.1056/nejmoa1509981
• 发表时间: 2016-01-28
• 期刊: The New England journal of medicine
• 作者: Byrd JC;Harrington B;O'Brien S;Jones JA;Schuh A;Devereux S;Chaves J;Wierda WG;Awan FT;Brown JR;Hillmen P;Stephens DM;Ghia P;Barrientos JC;Pagel JM;Woyach J;Johnson D;Huang J;Wang X;Kaptein A;Lannutti BJ;Covey T;Fardis M;McGreivy J;Hamdy A;Rothbaum W;Izumi R;Diacovo TG;Johnson AJ;Furman RR
• 通讯作者: Furman RR

Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

新型 BTK 抑制剂 Acalabrutinib 在 B 细胞非霍奇金淋巴瘤犬模型中的临床前评估。

• 发表时间: 2016
• 影响因子: 3.7
• 作者: Harrington, Bonnie K;Gardner, Heather L;Izumi, Raquel;Hamdy, Ahmed;Rothbaum, Wayne;Coombes, Kevin R;Covey, Todd;Kaptein, Allard;Gulrajani, Michael;Van Lith, Bart;Krejsa, Cecile;Coss, Christopher C;Russell, Duncan S;Zhang, Xiaoli;Urie, Bridge
• 通讯作者: Urie, Bridge