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

项目摘要/摘要 概述：该奖项的目标是为黛博拉·斯蒂芬斯博士提供培训和指导研究 经验，将有助于她过渡到实验中的独立调查员角色 淋巴系统恶性肿瘤患者的治疗方法和抗癌机制。她 长期的职业目标是成为一名临床/转化性研究人员，为 影响我们对淋巴瘤的看法，并有助于改善患者的预后。 研究：复发/难治性慢性淋巴细胞白血病(CLL)和非霍奇金淋巴瘤(NHL) 常见的、无法治愈的恶性肿瘤，对癌症死亡率有很大影响。最近，小说有针对性地 治疗方法改善了临床结果。然而，产生治疗抵抗力的患者情况很差。 结果。这项拟议的研究旨在了解、预防和克服这种治疗抵抗。这 该提案包括两项临床试验，涉及合理的联合疗法，目的是机械地 预防治疗耐药。在拟议的临床试验中接受治疗的患者的纵向样本将 通过靶向和全外显子组测序进行分析。芝加哥大学开发的一种新的计算工具 犹他州将用于研究亚克隆癌细胞群体的进化。拟议中的试验引入了两个 可能改变目前CLL/NHL治疗模式的新颖合理的联合疗法。 相关研究将为BCR的反应和耐药机制提供新的见解 抑制剂组合，并识别生物标记物，以早期识别有复发风险的患者。这个 将合理设计的早期临床试验与分子研究相结合，以确定应答原因 抵抗将为斯蒂芬斯博士提供成为一名成功的临床翻译所需的培训 研究淋巴系统恶性肿瘤，并为获得学术独立的R级资助提供基础。 职业发展计划/环境：斯蒂芬斯博士是一位肿瘤学家，在翻译方面有很强的基础 淋巴系统恶性肿瘤领域的研究。K23研究生课程，有针对性的培训，研讨会 出席，以及有指导的研究经验将提供斯蒂芬斯博士需要的技能和经验 成为淋巴系统恶性肿瘤的独立研究人员。在这个奖项期间，斯蒂芬斯博士将获得新的 基因组和生物信息学分析的内容领域知识。她将在临床试验中获得实用技能 设计、管理、基因组分析以及与广泛的多学科协作 研究团队。斯蒂芬斯博士召集了一位经验丰富、国际公认的导师 他们将在转化型癌症研究方面提供指导。亨斯迈癌症研究所，一家NCI- 指定的综合癌症中心和犹他大学为 初级教师的发展和多学科癌症研究合作的无与伦比的机会。

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.