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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：
10681976
负责人：
BINGLIANG FANG
金额：
$ 9.72万
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/10681976
关键词：
Academic Medical Centers Antineoplastic Agents Area Biologic Characteristic 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 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.