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

项目总结/摘要 概述：该奖项的目标是为Deborah Stephens博士提供培训和指导研究 经验，这将有助于她过渡到一个独立的研究者的作用，在实验 淋巴恶性肿瘤患者对癌症治疗的抗性的治疗和机制。她 长期的职业目标是成为一名临床/翻译研究者，为临床研究贡献新知识。 领域，影响我们如何看待淋巴瘤，并有助于改善患者的结果。 研究：复发性/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。近日，针对 治疗改善了临床结果。然而，产生治疗抵抗的患者的 结果。拟议的研究旨在了解，预防和克服这种治疗阻力。这 该提案包括两项涉及合理联合治疗的临床试验，目的是从机制上 防止治疗抵抗。将从接受拟定临床试验治疗的患者中采集纵向样本， 通过靶向和全外显子组测序进行分析。一种新的计算工具， 犹他州将用于研究亚克隆癌细胞群的进化。拟议的审判引入了两个 新的和合理的组合疗法，可以改变目前的CLL/NHL治疗的范例。 相关研究将为BCR的应答和耐药机制提供新的认识 抑制剂组合，并鉴定用于早期鉴定有复发风险的患者的生物标志物。的 合理设计的早期临床试验与分子研究相结合，以确定反应原因 和耐药性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。 研究人员在淋巴恶性肿瘤，并提供R级资金的基础上获得学术独立。 职业发展计划/环境：Dr. Stephens是一名肿瘤学家，在翻译方面有着坚实的基础。 淋巴恶性肿瘤领域的研究。K23研究生课程，有针对性的培训，研讨会 出席，并指导研究经验将提供技能和经验博士斯蒂芬斯需要， 成为淋巴系统恶性肿瘤的独立研究者。在此期间，斯蒂芬斯博士将获得新的 基因组学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践技能 设计，管理，基因组分析，并与广泛的多学科合作 研究团队。斯蒂芬斯博士组建了一个经验丰富，国际公认的指导 该团队将为转化癌症研究提供指导。亨茨曼癌症研究所，一个NCI- 指定的综合癌症中心和犹他州大学提供了丰富的环境， 初级教师的发展和无与伦比的机会，多学科癌症研究合作。

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.