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

项目摘要/摘要 这个项目描述了一项为期5年的培训计划，目标是成为一名具有长期目标的内科科学家。 在转化型胸腔肿瘤学领域建立一个研究项目。申请人目前是 介入性肺科和胸科肿瘤科医学导师 为肺癌患者的治疗选择和监测开发生物标志物的研究。这个 这项提议的研究重点是开发分子标记，以更好地识别 将对PD1/PDL1疗法做出反应，以避免不必要的毒性，降低成本，并实现更多 提供适当的治疗方法。这一目标将通过三个相辅相成的具体目标来实现。在……里面 特定目标1，将对晚期肺癌的肿瘤组织进行mRNA表达分析 接受抗PD1治疗的患者确定特定基因信号与治疗的相关性 回应。在具体目标2中，一种获取新的组织样本用于免疫表型鉴定的新方法将是 用于前瞻性地确定深层T细胞表型和功能分析的预测能力 用多参数流式细胞术检测抗PD1/PDL1治疗的反应。在具体目标3中，一个新的 将利用开发的能够定量测量循环PDL1外切体的技术 确定治疗前和治疗中PDL1外体表达水平的相关性以预测 接受检查点封锁的非小细胞肺癌患者的临床结果。培训部分 这一建议包括正式的课程作业，参与丰富的环境中的博士后讲座 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，他是加州大学胸科肿瘤实验室的主任 他是宾夕法尼亚州阿布拉姆森癌症中心肺部卓越翻译中心的联席主任 癌症免疫生物学和Anil Vachani博士，他是该部门的临床研究主任 宾夕法尼亚大学介入肺病学和胸科肿瘤学。Albelda博士和Vachani博士指导了 100名实习生。此外，一个由杰出科学家组成的咨询委员会将提供实验 在本奖项的有效期内提供帮助、智力指导和职业建议。

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.