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.

项目摘要/摘要 基于对成为临床科学家的持续承诺的历史，该提议的目标是 成为翻译癌症研究和分子领域的独立研究者和领导者 指导性胰腺导管腺癌（PDAC）的精密医学试验。 PDAC影响超过50,000 每年在美国的人们，并将很快成为与癌症相关死亡的第二大主要原因。 在这种毁灭性疾病中增加生存的两种可行策略是：（1）增加对 潜在的治疗手术切除，（2）确定每个患者的最佳全身疗法 目前在诊所规定的代理商干部。为了评估这些策略，该提议基于 多中心，随机的II期临床试验，研究了侵略性手术的安全性和有效性 结合细胞毒性化学疗法后，可切除和局部晚期疾病的边界方法的方法， 放射线和免疫疗法。在此试验的背景下，我们还将评估一种新文化的能力 技术，称为类器官，提供可临床可用的分子数据并指导精度医学 方法。综上所述，该提案评估了一种治疗策略，该策略可能导致治疗方法 在新诊断的PDAC患者中又有20-40％的手术（每年10-20,000名美国公民）和 将评估为每个PDAC患者选择最佳全身疗法的工具，以提供耐用的生存。 为了促进向独立的过渡并在未来项目中实现领导才能，翻译研究 在奖励期间，将通过正式的职业发展计划对努力进行补充。这个计划是 在伊丽莎白·贾菲（Elizabeth Jaffee）博士的指导下，他是转化研究领域的著名领导者 PDAC和约翰霍普金斯大学（JHU）综合癌症中心副主任。作为 由何种志愿的研究人员在以免疫为中心和分子引导的临床试验方面具有专业知识，博士 贾菲是理想的心理。已经成立了一个咨询委员会，以包括全球领先的专家 PDAC类器官，David Tuveson博士以及外科科学计划的领导者Christopher Wolfgang博士。我 已经加入了手术肿瘤学的分区，作为外科医生科学家，受到75％的保护时间。这 研究与培训计划将在JHU完成，JHU是世界上胰腺领域的主要机构之一 癌症护理和排名最高的研究机构。在JHU的丰富环境和资源中，我将购买 新型翻译研究和临床试验的设计和行为中的教学课程。到达 作为外科医生科学家的独立性，我还将利用正式的K-TO-R转型计划的资源 由JHU临床和转化研究所管理。通过K08职业的支持 发展奖计划对于帮助我实现担任领导者的长期目标至关重要 在分子引导的精密医学试验中，有可能重新定义PDAC的结果。