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

研究项目1：基于PDX的精准医疗治疗KRAS突变肺癌试验

基本信息

批准号：
10242644
负责人：
BINGLIANG FANG
金额：
$ 25.21万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242644
关键词：
Academic Medical Centers Antineoplastic Agents Area Biologic Characteristic Biological Biological Markers CDKN2A gene Cancer Patient Clinical Clinical Trials Coenzyme A Ligases Collaborations Complex Coupled DNA Sequence Alteration Data Development Drug Combinations Drug Targeting Failure Family member Gene Amplification Genomics Goals Growth Factor Receptors Human Investigational Drugs Joints KRAS oncogenesis KRAS2 Gene Mutation KRAS2 gene Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Medical center MicroRNAs Mitogen-Activated Protein Kinase Kinases Modeling Molecular Molecular Abnormality Moon Mutation Non-Small-Cell Lung Carcinoma Normal Cell Nuclear Export Oncogenes Outcome Patient-Focused Outcomes Patients Positioning Attribute Precision medicine trial Precision therapeutics Predisposition Primary Neoplasm Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt Public Health Quality of life RAS genes Radiation therapy Reporting Research Research Project Grants Resistance STK11 gene Signal Transduction Solid Neoplasm Subgroup System TP53 gene Testing Texas Therapeutic Therapeutic Agents Therapeutic Effect Therapy Evaluation Translating Universities anticancer activity base cancer biomarkers cancer cell cancer therapy cancer type chemotherapy clinically relevant docetaxel druggable target early phase clinical trial fatty acid oxidation improved ineffective therapies inhibitor/antagonist innovation kinase inhibitor lung tumorigenesis molecular marker molecular subtypes mutant next generation sequencing novel therapeutic intervention overexpression patient derived xenograft model pre-clinical precision medicine predictive marker programs receptor response screening small molecule small molecule libraries success targeted treatment therapeutic development therapeutically effective transcription factor treatment responders treatment response tumor

项目摘要

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.

抽象的该项目的目标是开发有效的精准医学来治疗 KRAS 突变非小细胞肺癌通过确定分子特征的患者来源异种移植物的反应来治疗细胞肺癌（NSCLC） (PDX) 模型具有或不具有针对靶向治疗药物的 KRAS 突变。将优先考虑 NCI 研究性新药（NCI-IND 药物）组合中的药物可提高早期阶段的成功率 KRAS 突变 NSCLC 患者的临床试验。本研究的中心假设是，大量一组经过充分表征的 KRAS 突变 NSCLC PDX，概括了生物学的多种特征人类 KRAS 突变癌症的背景将为识别有效的治疗方法提供临床前平台 KRAS 突变非小细胞肺癌的策略和能够识别治疗反应者的分子生物标志物。已知 KRAS 基因的激活突变是与以下疾病相关的主要基因组改变之一：肺腺癌。迄今为止，KRAS 突变非小细胞肺癌的治疗仍然是一个未得到满足的医疗需求。而且，活性抗癌药物的开发面临因缺乏临床前肿瘤而导致的高失败率的挑战模型高度预测人类的治疗效果以及识别临床反应者的生物标志物试验。我们将通过确定靶向药物的治疗活性并识别来克服这一挑战能够在临床和分子水平上识别这些药物的反应者的潜在预测生物标志物注释源自 NSCLC 的 PDX 模型。我们的研究团队在建立 NSCLC 方面拥有丰富的专业知识 PDX，对 PDX 和原发性肿瘤进行分子表征，开发非小细胞肺癌 (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。我们已经生成了 190 例 NSCLC PDX 和 82 个 PDX（22% 具有致癌 KRAS 突变）的完整基因组特征及其各自的原发肿瘤。我们的团队齐心协力，将为实现总体目标做出重大贡献 NCI 的 PDXNet 生成 PDX 模型数据，以支持精准治疗的早期临床试验。到为此，我们提出了三个具体目标：1）利用 KRAS 确定 NSCLC PDX 的分子亚型突变； 2) 确定有或没有 KRAS 突变的 NSCLC PDX 模型对治疗的反应批准供患者使用的研究性新药，优先考虑 NCI-IND 药物； 3) 表征分子生物标志物以及分子亚型和治疗反应之间的机制关系。拟议的研究与 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基因定义的肿瘤亚组，探索遗传异常与肿瘤反应的相关性； 2) 有助于的机制 PDX 模型对治疗药物的敏感性或耐药性。拟议研究的成功将导致针对 KRAS 突变肺癌的有效精准治疗，目前的治疗方法对此无效。