Novel Strategies to Eliminate Resistance to B-cell Receptor Inhibitor Therapy in Lymphoid Malignancies

消除淋巴恶性肿瘤 B 细胞受体抑制剂治疗耐药性的新策略

• 批准号: 9761500
• 负责人: DEBORAH STEPHENS
• 金额: $ 18.04万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761500
• 关键词: 1-Phosphatidylinositol 3-Kinase; Agammaglobulinaemia tyrosine kinase; Area; Award; B-Cell NonHodgkins Lymphoma; Binding Sites; Bioinformatics; Biological; Cell Death; Cell Line; Cells; Cessation of life; Chronic; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Clinical Trials Design; Clonal Evolution; Collaborations; Combined Modality Therapy; Complex; Comprehensive Cancer Center; Correlative Study; Data; Development; Development Plans; Dose; Drug Combinations; Drug Kinetics; Early identification; Ensure; Environment; Evolution; Faculty; Foundations; Funding; Genomics; Goals; Growth; Individual; Institutes; Interdisciplinary Study; International; Investigational Therapies; Knowledge; Lymphoma; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Mentors; Modeling; Molecular; Monoclonal Antibodies; Mutation; Myeloid Leukemia; NR0B2 gene; Non-Hodgkin' s Lymphoma; Oncologist; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phase; Play; Population; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Regimen; Relapse; Research; Research Personnel; Resistance; Resistance development; Role; Safety; Sampling; Signal Pathway; Signaling Molecule; Testing; Training; Translational Research; Treatment Efficacy; Tyrosine Kinase Inhibitor; Universities; Utah; Work; anticancer research; base; cancer cell; cancer therapy; career; career development; chemotherapy; chronic lymphocytic leukemia cell; computerized tools; design; drug metabolism; drug sensitivity; early detection biomarkers; exome sequencing; experience; exportin 1 protein; improved; improved outcome; inhibitor/antagonist; insight; mortality; mouse model; multidisciplinary; new therapeutic target; novel; novel strategies; outcome forecast; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; prevent; relapse risk; resistance mechanism; response; skills; targeted agent; targeted sequencing; targeted treatment; therapeutic target; therapy development; therapy resistant; translational cancer research; translational scientist

PROJECT SUMMARY/ABSTRACT Overview: The goal of this award is to provide Dr. Deborah Stephens, with training and mentored research experiences that will facilitate her transition into the role of an independent investigator in experimental therapeutics and mechanisms of resistance to cancer therapies for patients with lymphoid malignancies. Her long-term career goal is to become a clinical/translational investigator who contributes new knowledge to the field, impacts how we think about lymphoma, and helps to improve patient outcomes. Research: Relapsed/refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHLs), are common, incurable malignancies that contribute significantly to cancer mortality. Recently, novel targeted therapies have improved clinical outcomes. However, patients who develop therapy resistance have very poor outcomes. The proposed research aims to understand, prevent, and overcome this therapy resistance. This proposal includes two clinical trials that involve rational combination therapies with the aim to mechanistically prevent treatment resistance. Longitudinal samples from patients treated on the proposed clinical trials will be analyzed by targeted and whole exome sequencing. A novel computational tool developed at the University of Utah will be used to study the evolution of sub-clonal cancer cell populations. The proposed trials introduce two novel and rational combination therapies that could change the current paradigm of CLL/NHL therapy. Correlative studies will provide new insights into the mechanisms governing response and resistance to BCR inhibitor combinations, and identify biomarkers for early identification of patients at risk of relapse. The combination of rationally designed early clinical trials with molecular studies to identify the causes of response and resistance will provide Dr. Stephens with the training needed to become a successful clinical translational researcher in lymphoid malignancies and provide the basis for R-level funding to gain academic independence. Career Development Plan/Environment: Dr. Stephens is an oncologist with a strong foundation in translational research in the field of lymphoid malignancies. The K23 graduate coursework, targeted training, seminar attendance, and mentored research experiences will provide the skills and experiences Dr. Stephens needs to become an independent investigator in lymphoid malignancies. During this award, Dr. Stephens will acquire new content area knowledge in genomic and bioinformatics analysis. She will gain practical skills in clinical trial design, management, genomic analysis, and working collaboratively with an extensive multi-disciplinary research team. Dr. Stephens has assembled a highly experienced and internationally-recognized mentoring team, who will provide guidance in translational cancer research. The Huntsman Cancer Institute, an NCI- designated Comprehensive Cancer Center and the University of Utah provide a rich environment for the development of junior faculty and unparalleled opportunities for multidisciplinary cancer research collaborations.

项目摘要/摘要 概述：该奖项的目标是向Deborah Stephens博士提供培训和修改研究 将促进她过渡到独立研究者在实验中的作用的经验 淋巴瘤患者对癌症疗法抗药性的治疗和机制。她 长期职业目标是成为一名临床/转化调查员，为新知识做出新知识 场，影响我们对淋巴瘤的看法，并有助于改善患者的结局。 研究：复发/难治性慢性淋巴细胞性白血病（CLL）和非霍奇金的淋巴瘤（NHLS）是 常见的，无法治愈的损害，对癌症死亡产生了重大贡献。最近，新颖的目标 疗法改善了临床结果。但是，耐药性的患者非常差 结果。拟议的研究旨在理解，预防和克服这种耐药性。这 提案包括两个临床试验，涉及合理组合疗法，目的是机械化 防止治疗性。在拟议的临床试验中接受治疗的患者的纵向样本将是 通过靶向和整个外显子组测序分析。在大学开发的一种新颖的计算工具 犹他州将用于研究亚克隆癌细胞群体的演变。拟议的试验引入了两个 可以改变CLL/NHL治疗的当前范式的新型和理性组合疗法。 相关研究将提供有关管理反应和对BCR抗性的机制的新见解 抑制剂组合，并鉴定生物标志物，以早日鉴定出患有退休风险的患者。 合理设计的早期临床试验与分子研究的结合，以确定反应的原因 阻力将为斯蒂芬斯博士提供成为成功临床翻译所需的培训 淋巴性恶性肿瘤的研究人员为R级资助提供了学术独立性的基础。 职业发展计划/环境：Stephens博士是一名肿瘤学家，在翻译方面具有坚实的基础 淋巴恶性肿瘤领域的研究。 K23研究生课程，有针对性的培训，开创性 出勤和修改研究经验将为斯蒂芬斯博士提供的技能和经验提供 成为淋巴恶性肿瘤的独立研究者。在此奖项期间，斯蒂芬斯博士将获得新的 基因组和生物信息学分析中的内容领域知识。她将获得临床试验的实用技能 设计，管理，基因组分析和与广泛的多学科合作 研究团队。斯蒂芬斯博士组建了经验丰富且具有国际认可的心理 团队，将为翻译癌症研究提供指导。亨斯曼癌症研究所，NCI- 指定的综合癌症中心和犹他大学为 开发初级教师和无与伦比的跨学科癌症研究合作的机会。