Research Project 1: PDX-based trials of precision medicine for treatment of KRAS mutant lung cancers

摘要 该项目的目标是开发有效的精准医学，用于治疗KRAS突变型非小细胞肺癌。 通过确定分子表征的患者来源的异种移植物的应答来治疗非小细胞肺癌（NSCLC） (PDX)具有或不具有KRAS突变的模型与靶向治疗剂。将优先考虑 NCI研究性新药（NCI-IND药物）组合中的药物，以提高早期阶段的成功率 KRAS突变型NSCLC患者的临床试验。这项研究的中心假设是， 一组充分表征的KRAS突变型NSCLC PDX，其概括了生物学特性的多种特征， 人类KRAS突变型癌症的背景将为确定有效的治疗方法提供临床前平台。 KRAS突变型NSCLC的治疗策略和能够识别治疗应答者的分子生物标志物。 已知KRAS基因的激活突变是与以下相关的主要基因组改变之一： 肺腺癌到目前为止，KRAS突变型NSCLC的治疗仍然是一个未满足的医疗需求。此外，委员会认为， 活性抗癌药物的开发受到缺乏临床前肿瘤治疗所导致的高失败率的挑战 高度预测人类治疗效果和识别临床应答者的生物标志物的模型 审判我们将通过确定靶向药物的治疗活性和识别 潜在的预测性生物标志物，能够在临床和分子水平上识别对这些药物的应答者， 源自NSCLC的注释的PDX模型。我们的研究团队在建立NSCLC方面具有广泛的专业知识 PDX，分子表征PDX和原发性肿瘤，开发NSCLC的新治疗策略， 并将有效的临床前治疗策略转化为临床试验。我们已经产生了190个NSCLC PDX和82个PDX（22%具有致癌KRAS突变）的完整基因组表征及其 原发性肿瘤。我们的团队将共同为实现总体目标做出重大贡献 NCI的PDXNet用于生成PDX模型数据，以支持精准疗法的早期临床试验。到 为此，我们提出了三个具体目标：1）用KRAS确定NSCLC PDX分子亚型 突变; 2）确定具有或不具有KRAS突变的NSCLC PDX模型对以下治疗的响应： 批准用于患者使用的研究性新药，优先考虑NCI-IND药物;以及3）表征 分子生物标志物和分子亚型与治疗反应之间的机制关系。 建议的研究与NCI的PDX开发和试验的以下研究领域高度相关 中心：1）基于机制的药物组合治疗遗传定义的肿瘤亚组， 探索遗传异常与肿瘤反应的相关性;和2）有助于 PDX模型对治疗剂的敏感性或抗性。拟议研究的成功将导致 针对KRAS突变型肺癌的有效精确治疗，目前的治疗方法对此无效。

Abstract The objective of this project is to develop effective precision medicine for treatment of KRAS-mutant non-small cell lung cancer (NSCLC) by determining responses of molecularly characterized patient-derived xenograft (PDX) models with or without KRAS mutations to targeted therapeutic agents. The priority will be given to the agents in the NCI Investigational New Drugs (NCI-IND agents) portfolio to increase the success of early-phase clinical trials in patients with KRAS-mutant NSCLCs. The central hypothesis of the proposed study is that a large set of well-characterized KRAS-mutant NSCLC PDXs that recapitulate multiple characteristics of the biological context of human KRAS-mutant cancers will provide a preclinical platform for identifying effective therapeutic strategies for KRAS-mutant NSCLC and molecular biomarkers capable of identifying treatment responders. Activating mutations of the KRAS gene are known to be among the major genomic alterations associated with lung adenocarcinoma. Thus far, treatment of KRAS-mutant NSCLC remains an unmet medical need. Moreover, development of active anticancer drugs is challenged by high failure rates caused by a lack of preclinical tumor models highly predictive of therapeutic effects in humans and of biomarkers that identify responders in clinical trials. We will overcome this challenge by determining the therapeutic activities of targeted drugs and identifying potential predictive biomarkers capable of identifying responders to those agents in clinically and molecularly annotated PDX models derived from NSCLC. Our research team has extensive expertise in establishing NSCLC PDXs, molecularly characterizing PDXs and primary tumors, developing novel therapeutic strategies for NSCLC, and translating effective preclinical therapeutic strategies for clinical trials. We have generated 190 NSCLC PDXs and completed genomic characterization of 82 PDXs (22% with oncogenic KRAS mutations) and their respective primary tumors. Together, our team is positioned to make a major contribution to the overall objectives of the NCI's PDXNet to generate data on PDX models to support early clinical trials of precision therapies. To that end, we propose three specific aims: 1) determine molecular subtypes of NSCLC PDXs with KRAS mutations; 2) determine responses of NSCLC PDX models with or without KRAS mutations to treatment with investigational new drugs approved for patient use, with priority given to the NCI-IND agents; and 3) characterize molecular biomarkers and the mechanistic relationship between molecular subtypes and treatment responses. The proposed studies are highly relevant to the following Research Areas of NCI's PDX Development and Trial Centers: 1) mechanism-based drug combinations in treatment of genetically defined tumor subgroups that explore the correlation of genetic abnormalities with tumor response; and 2) mechanisms that contribute to the sensitivity or resistance of PDX models to therapeutic agents. The success of the proposed studies will lead to effective precision therapy for KRAS-mutant lung cancers, for which current therapies are ineffective.