Personalized preclinical models in pancreas cancer: a tractable approach to precision medicine

项目摘要/摘要 建立在成为临床科学家的持续承诺的历史基础上，这项提议的目标是 成为翻译癌症研究和分子领域的独立研究员和领导者- 胰腺导管腺癌(PDAC)的精确医学指导试验。PDAC影响超过50,000 美国每年都有癌症患者死亡，并将很快成为癌症相关死亡的第二大原因。 在这种毁灭性疾病中提高存活率的两个易于处理的策略是：(1)增加对 潜在的根治性手术切除，以及(2)确定每个患者的最佳系统治疗方案 目前在诊所开药方的一批药剂。为了评估这些战略，本提案基于 一项多中心、随机、II期临床试验，研究侵袭性手术的安全性和有效性 联合细胞毒化疗后边缘可切除局部晚期病变的探讨 放射治疗和免疫治疗。在这次审判的背景下，我们还将评估一种新文化的能力 技术，称为有机化合物，提供临床可操作的分子数据并指导精确医学 接近了。综上所述，这项建议评估了一种可能导致治愈的治疗策略 为另外20%-40%的新诊断的PDAC患者(每年10-20,000名美国公民)和 将评估一种工具，为每个PDAC患者选择最佳的系统治疗，以提供持久的生存。 为了促进向独立的过渡，并在未来的项目中发挥领导作用，翻译研究 在颁奖期间，将以正式的职业发展计划补充努力。这个计划是 在伊丽莎白·贾菲博士的指导下，她是翻译研究领域的著名领导者 约翰霍普金斯大学(JHU)综合癌症中心副主任。作为一种 在以免疫为重点和分子指导的临床试验方面拥有专业知识的外部资助的研究人员，Dr。 贾菲是一位理想的导师。已经成立了一个咨询委员会，将世界领先的专家包括在内 PDAC有机化合物，David Tuveson博士和外科科学倡议的领导者Christopher Wolfgang博士。我 以外科科学家的身份加入外科肿瘤科，拥有75%的受保护研究时间。这个 研究和培训计划将在JHU完成，JHU是世界领先的胰腺研究机构之一 癌症护理和一流的研究机构。在锦州大学丰富的环境和资源中，我将追求 在设计和实施新的转译研究和临床试验方面的教学课程。要达到 独立作为一名外科医生兼科学家，我还将利用正式的从K到R过渡计划的资源 由JHU临床和翻译研究所管理。在K08职业生涯中提供支持 发展奖计划将是帮助我实现作为领导者的长期目标的关键 在分子引导的精确医学试验中，有可能重新定义PDAC的结果。

Project Summary/Abstract Built upon a history of sustained commitment to becoming a clinician scientist, the goal of this proposal is to become an independent investigator and leader in the field of translational cancer research and molecularly- guided precision medicine trials in pancreatic ductal adenocarcinoma (PDAC). PDAC impacts over 50,000 people annually in the United States and will soon become the second leading cause of cancer-related death. Two tractable strategies to increase survival in this devastating disease are: (1) to increase the utilization of potentially curative surgical resection, and (2) to identify the optimal systemic therapy for each patient amongst the cadre of agents currently prescribed in the clinic. To evaluate these strategies, this proposal is based upon a multi-center, randomized, phase II clinical trial investigating the safety and efficacy of an aggressive surgical approach to borderline resectable and locally advanced disease after combination cytotoxic chemotherapy, radiation, and immunotherapy. In the context of this trial, we will also evaluate the capacity of a novel culture technique, termed organoids, to provide clinically-actionable molecular data and guide precision medicine approaches. Taken together, this proposal evaluates a treatment strategy that may result in a curative operation for an additional 20-40% of newly diagnosed PDAC patients (10 - 20,000 US citizens annually) and will evaluate a tool for selection of best systemic therapy for each PDAC patient to provide a durable survival. To foster a transition to independence and enable leadership in future projects, translational research efforts will be supplemented during the award period with a formal career development plan. This plan is guided by the mentorship of Dr. Elizabeth Jaffee, a renowned leader in the field of translational research in PDAC and the deputy director of the Comprehensive Cancer Center at Johns Hopkins University (JHU). As an extramurally-funded researcher with an expertise in immune-focused and molecularly-guided clinical trials, Dr. Jaffee is an ideal mentor. An advisory committee has been established to include the world’s leading expert in PDAC organoids, Dr. David Tuveson, and a leader in surgical science initiatives, Dr. Christopher Wolfgang. I have joined the Division of Surgical Oncology as a surgeon-scientist with 75% protected research time. The research and training plan will be completed at JHU, one of the world’s leading institutions for pancreatic cancer care and a top-ranked research institution. In the rich environment and resources of JHU, I will pursue didactic coursework in the design and conduct of novel translational research and clinical trials. To reach independence as a surgeon-scientist, I will also draw upon the resources of a formal K-to-R transition program administered by the JHU Institute for Clinical and Translational Research. Support through the K08 Career Development Awards Program will be critical in helping me to achieve a long-term goal of serving as a leader in molecularly-guided precision medicine trials that have the potential to redefine outcomes in PDAC.