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

项目总结/摘要 建立在持续承诺成为临床科学家的历史基础上，本提案的目标是 成为一个独立的研究者和领导者，在转化癌症研究和分子- 指导胰腺导管腺癌（PDAC）的精准医学试验。PDAC影响超过5万人 在美国，每年有100万人死于癌症，很快将成为癌症相关死亡的第二大原因。 提高这种毁灭性疾病生存率的两个易于处理的策略是：（1）增加对 潜在的治愈性手术切除，以及（2）确定每个患者的最佳全身治疗， 目前在诊所开处方的药物骨干。为了评估这些战略，本建议基于 一项多中心、随机、II期临床试验，研究了积极手术的安全性和有效性， 联合细胞毒化疗后的边缘可切除和局部晚期疾病的方法， 放射和免疫疗法在这个试验的背景下，我们也将评估一个新的文化的能力， 技术，称为类器官，以提供临床可操作的分子数据和指导精准医疗 接近。综上所述，该建议评估了一种治疗策略，可能导致治愈性 为另外20-40%的新诊断PDAC患者（每年10 - 20，000名美国公民）进行手术， 将评估一种工具，用于为每个PDAC患者选择最佳全身治疗，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，转化研究 在授标期间，还将制定正式的职业发展计划。这个计划是 在转化研究领域著名领导者伊丽莎白·贾菲博士的指导下， PDAC和约翰霍普金斯大学（JHU）综合癌症中心副主任。作为 作为一名在免疫学和分子指导的临床试验方面具有专长的校外资助的研究人员， 贾菲是一个理想的导师。成立了一个咨询委员会，包括世界领先的专家， PDAC类器官，大卫Tuveson博士和外科科学倡议的领导者，克里斯托弗沃尔夫冈博士。我 作为外科医生科学家加入了外科肿瘤科，有75%的研究时间受到保护。的 研究和培训计划将在JHU完成，JHU是世界领先的胰腺癌研究机构之一， 癌症治疗和一流的研究机构。在JHU丰富的环境和资源中，我将追求 在设计和进行新的转化研究和临床试验的教学课程。达成 作为一名外科医生兼科学家，我还将利用一个正式的从知识到知识的过渡计划的资源 由JHU临床和转化研究所管理。通过K 08职业生涯支持 发展奖励计划对帮助我实现作为领导者的长期目标至关重要 在分子引导的精准医学试验中，这些试验有可能重新定义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.