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

胰腺癌的个性化临床前模型：一种易于处理的精准医疗方法

• 批准号: 10372089
• 负责人: Richard Andrew Burkhart
• 金额: $ 26.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372089
• 关键词: Advisory Committees; Aftercare; Award; Basic Science; Biological Markers; Biology; Biopsy; Cancer Biology; Cancer Center; Cancer Etiology; Caring; Cell Line; Cessation of life; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Oncology; Clinical Research; Clinical Treatment; Clinical Trials; Clinical Trials Design; Colon Carcinoma; Combined Modality Therapy; Comprehensive Cancer Center; Culture Techniques; Cytotoxic Chemotherapy; Data; Development; Development Plans; Diagnosis; Disease; Disease model; Environment; Excision; Exposure to; Extramural Activities; Fostering; Foundations; Funding; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic; Genotype; Glean; Goals; Guidelines; Heterogeneity; Image; Immune; Immunotherapy; In Vitro; Individual; Institutes; Institution; K-Series Research Career Programs; Knowledge; Laboratories; Leadership; Life; Losartan; Malignant neoplasm of pancreas; Mentors; Mentorship; Methods; Microsatellite Instability; Modeling; Molecular; Newly Diagnosed; Nivolumab; Operating Rooms; Operative Surgical Procedures; Organoids; Outcome; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Pre-Clinical Model; Precision medicine trial; Precision therapeutics; Primary Neoplasm; Radiation; Radiation therapy; Randomized; Recommendation; Recording of previous events; Recurrence; Research; Research Personnel; Research Training; Resectable; Resected; Resources; Role; Safety; Science; Scientist; Speed; Surgeon; Surgical Oncology; Systemic Therapy; Testing; Therapeutic; Time; Translational Research; United States; Universities; Unresectable; Work; advanced disease; base; cancer care; career development; chemotherapy; clinically actionable; clinically relevant; design; drug sensitivity; experience; four-arm trial; hormone therapy; immunohistochemical markers; improved; malignant breast neoplasm; molecular marker; novel; novel therapeutics; operation; patient derived xenograft model; patient oriented; patient screening; personalized therapeutic; precision medicine; programs; recruit; response; tool; translational cancer research; treatment response; treatment strategy; tumor; tumor heterogeneity; two-dimensional

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.

项目概要/摘要 建立在持续致力于成为一名临床科学家的历史之上，该提案的目标是 成为转化癌症研究和分子生物学领域的独立研究者和领导者 指导胰腺导管腺癌（PDAC）精准医学试验。 PDAC 影响超过 50,000 人 在美国每年都有人死于癌症，并且很快将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生存率的两种可行策略是：（1）增加对 潜在治愈性手术切除，以及（2）确定每位患者的最佳全身治疗 目前在诊所开处方的代理人队伍。为了评估这些策略，本提案基于 一项多中心、随机、II 期临床试验，调查积极手术的安全性和有效性 联合细胞毒化疗后治疗临界可切除和局部晚期疾病的方法， 放射治疗和免疫治疗。在这次试验的背景下，我们还将评估一种新颖文化的能力 称为类器官的技术，提供临床上可行的分子数据并指导精准医疗 接近。总而言之，该提案评估了可能产生治愈效果的治疗策略 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，以及 将评估为每位 PDAC 患者选择最佳全身治疗的工具，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、转化研究中发挥领导作用 在奖励期间，将通过正式的职业发展计划来补充努力。这个计划是 在伊丽莎白·贾菲 (Elizabeth Jaffee) 博士的指导下，她是转化研究领域的著名领导者 PDAC 兼约翰霍普金斯大学 (JHU) 综合癌症中心副主任。作为一个 博士是一位获得校外资助的研究人员，在以免疫为中心和分子指导的临床试验方面拥有专业知识。 Jaffee 是一位理想的导师。已经成立了一个咨询委员会，其中包括世界领先的专家 PDAC 类器官的 David Tuveson 博士和外科科学倡议的领导者 Christopher Wolfgang 博士。我 已作为外科医生科学家加入肿瘤外科部门，并拥有 75% 的受保护研究时间。这 研究和培训计划将在约翰霍普金斯大学完成，约翰霍普金斯大学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JHU丰富的环境和资源中，我将追求 新颖的转化研究和临床试验的设计和实施的教学课程。达到 作为一名外科医生科学家的独立性，我还将利用正式的 K 到 R 过渡计划的资源 由约翰霍普金斯大学临床与转化研究所管理。通过 K08 职业提供支持 发展奖励计划对于帮助我实现担任领导者的长期目标至关重要 分子引导的精准医学试验有可能重新定义 PDAC 的结果。