A multimodal approach to develop molecular markers to predict response to immune targeted agents in non-small cell lung cancer

项目总结/摘要 这个项目描述了一个5年的培训计划，作为一个长期目标的医生，科学家的职业生涯 在转化型胸部肿瘤学领域建立一个研究项目。申请人目前 介入肺科和胸肿瘤科的医学讲师， 研究开发用于治疗选择和监测肺癌患者的生物标志物。的 该建议的研究重点是开发分子标记物，以更好地识别 将对PD 1/PDL 1治疗作出反应，以避免不必要的毒性，降低成本，并使更多 提供适当的治疗。这一目标将通过三个相辅相成的具体目标来实现。在 具体目标1，将对晚期肺癌的肿瘤组织进行mRNA表达分析 接受抗PD 1治疗的患者，以确定特定基因特征与治疗的相关性 反应在特定目标2中，将采用一种新的方法获取新鲜组织样本进行免疫表型分析。 用于前瞻性地确定深层T细胞表型和功能测定预测 使用多参数流式细胞术检测对抗PD 1/PDL 1治疗的应答。在具体目标3中， 将利用一种能够定量测量循环PDL 1外泌体的已开发技术 确定治疗前和治疗中外泌体PDL 1表达水平的相关性， 接受检查点阻断的非小细胞肺癌患者的临床结局。培训部分 这项建议包括正式的课程，在博士后讲座丰富的环境参与， 胸部肿瘤学/肿瘤免疫学，获得先进的实验室技术（重点是 生物信息学和先进的流式细胞术），以及个人指导。该项目将在 史蒂文·阿尔贝尔达博士的监督，他是芝加哥大学胸部肿瘤实验室的主任。 宾夕法尼亚州和联合主任艾布拉姆森癌症中心的卓越转化中心肺 Anil Vachani博士，他是癌症免疫生物学科的临床研究主任， 宾夕法尼亚大学介入肺科和胸部肿瘤学。阿尔伯达医生和瓦查尼医生 100名学员。此外，由杰出科学家组成的咨询委员会将提供实验性的 协助，智力指导，并在此奖项的整个期间的职业建议。

PROJECT SUMMARY/ABSTRACT This project describes a 5 year training program for a career as a physician-scientist with the long term goal of establishing a research program within the field of translational thoracic oncology. The applicant is currently an Instructor of Medicine in the Section of Interventional Pulmonology and Thoracic oncology conducting research in developing biomarkers for the treatment selection and monitoring of patients with lung cancer. The research focus of this proposal is to develop molecular markers to better identify the subgroup of patients that will respond to PD1/PDL1 therapies in order to avoid unnecessary toxicities, reduce costs, and enable more appropriate therapies to be delivered. This goal will be accomplished in three complementary specific aims. In Specific Aim 1, mRNA expression analyses will be performed on tumor tissue from advanced lung cancer patients treated with anti-PD1 therapy to determine the association of specific gene signatures with treatment response. In Specific Aim 2, a novel approach to acquire fresh tissue samples for immunophenotyping will be utilized to prospectively determine the ability of deep T cell phenotyping and functional assays to predict response to anti-PD1/PDL1 therapy using multi-parametric flow cytometry. In Specific Aim 3, a newly developed technique that enables the quantitative measurement of circulating PDL1 exosomes will be utilized to determine the association of pretreatment and on-treatment exosomal PDL1 expression levels to predict clinical outcomes in non-small cell lung cancer patients receiving checkpoint blockade. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures in thoracic oncology/tumor immunology, acquisition of advanced laboratory techniques (with a focus on bioinformatics and advanced flow cytometry), and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of the Thoracic Oncology Laboratory at the University of Pennsylvania and Co-Director of the Abramson Cancer Center’s Translational Center of Excellence for Lung Cancer Immunobiology, and Dr. Anil Vachani who is the Director of Clinical Research for the Section of Interventional Pulmonology and Thoracic Oncology at Penn. Dr. Albelda and Dr. Vachani have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.