A biomarker-driven strategy to guide the use of radiotherapy in non-small cell lung cancer

指导非小细胞肺癌放疗使用的生物标志物驱动策略

基本信息

批准号：
10089004
负责人：
Mohamed E. Abazeed
金额：
$ 36.14万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-08 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089004
关键词：
Accounting Adoption Architecture BRAF gene Biological Markers Biopsy Specimen Cancer Etiology Cancer Patient Cancer cell line Catalogs Catalytic Domain Categories Cell Survival Cells Cessation of life Chemicals Clinical Clinical Research Clinical Trials Collection Complement Data Dependence Drug Combinations Evolution Experimental Models Frequencies Gene Expression Genetic Genetic Determinism Genetic Variation Geography Goals Immunofluorescence Immunologic Individual Investigation Lead Lung Neoplasms MEKs Malignant Neoplasms Malignant neoplasm of lung Measures Methods Minor Modeling Molecular Mutation NF-E2-related factor 2 Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome PIK3CA gene Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphatidylinositols Phosphotransferases Proto-Oncogene Proteins B-raf Radiation Radiation Tolerance Radiation therapy Radiosensitization Recurrence Regimen Research Resistance Role Sampling Technology Testing Therapeutic Time Translations Tumor Cell Line United States Variant Work actionable mutation base biomarker-driven cancer cell cancer type chemoradiation chemotherapy clinical translation clinically actionable exome sequencing experimental study genetic variant genomic data in vivo individual patient inhibitor/antagonist innovation kinase inhibitor mathematical model mortality mouse model neoplastic cell novel therapeutics outcome prediction palliative programs radiation resistance radiation response radioresistant response standard of care targeted treatment tumor tumor DNA

项目摘要

There is an urgent need to nominate biomarkers that are likely to predict the efficacy of radiotherapy and accelerate their clinical translation. Efforts thus far have been limited in large part because the genetic features regulating tumor cell survival and their frequency across and within individual cancer types had not been studied on a large-scale. Our group completed the largest profiling effort of survival after radiation in cancer cell lines, comprising a diverse collection of 533 genetically annotated tumor cell lines from 26 cancer types. To complement this work, we recently initiated the systematic profiling of >1000 genetic variants that could potentially contribute to the resistance of cancer cells to radiation. We combined results from our profiling efforts to identify features that predict the resistance of lung cancer cells to radiation. The objective in this investigation is to advance the clinical translation of two of the most important regulators of radiation resistance in lung cancer, Nrf2 and Braf. The Nrf2 pathway is genetically altered in ~28% of patients with non-small cell lung cancer (NSCLC) and cells with mutations in NFE2L2 or KEAP1 are the most highly correlated with resistance to radiation. To identify genetic dependencies of Nrf2-active tumors, we used computational and experimental approaches to demonstrate the frequent co-occurrence between Nrf2 and phosphoinositide 3-kinase (PI3K) alteration in NSCLCs. Using genetic and chemical means we show that antagonizing the catalytic subunit of PI3K, p110 (encoded by PIK3CA), decreases Nrf2 activity and reverses radiation resistance driven by this pathway. These results provide the rationale to advance a radiosensitization strategy for patients with Nrf2-active NSCLC by targeting PI3K. Our profiling efforts also demonstrate a critical role for BRAF, which is genetically altered in ~7% of patients with NSCLC, in the resistance of lung cancer cells to radiation. We show, for the first time, that BRAF kinase domain mutations confer resistance to radiation in lung cancers and that they, unlike Nrf2 pathway alterations, are almost invariably a minor component of the tumor (i.e. they are subclonal). We use mathematical and experimental models to show that clonal architecture has significant implications for the likelihood of response to targeted therapies and radiation. Together, these results provide a compelling rationale to examine the role of Nrf2 and Braf alterations in predicting outcomes after radiotherapy and advance a genomically-guided radiosensitization strategy for patients with these tumors. If these hypotheses are correct, our results will demonstrate that radiotherapeutic sensitizers can be selected based on both the identity and type (clonal v. subclonal) of genetic alterations identified in a patient's cancer, prompting an evolution in the use of radiation from a generic approach to one that is guided by the genetic composition of individual tumors.

迫切需要提名可能预测放疗疗效的生物标志物迄今为止，加速其临床转化的努力在很大程度上受到限制，因为遗传特征。尚未研究调节肿瘤细胞存活及其在个体癌症类型之间和内部的频率我们的团队完成了大规模的癌细胞系辐射后生存分析工作，包含来自 26 种癌症类型的 533 个基因注释肿瘤细胞系。为了补充这项工作，我们最近启动了超过 1000 个遗传变异的系统分析，这些变异可以可能有助于癌细胞对辐射的抵抗力。我们综合了我们的分析工作的结果。确定预测肺癌细胞对辐射的抵抗力的特征。是为了推进肺癌中两种最重要的抗辐射调节因子的临床转化， Nrf2 和 Braf 在约 28% 的非小细胞肺癌患者中发生基因改变。 (NSCLC) 和 NFE2L2 或 KEAP1 突变的细胞与耐药性最相关为了确定 Nrf2 活性肿瘤的遗传依赖性，我们使用了计算和实验。证明 Nrf2 和磷酸肌醇 3-激酶 (PI3K) 之间频繁共现的方法使用遗传和化学手段，我们表明拮抗 NSCLC 的催化亚基。 PI3K，p110（由 PIK3CA 编码），降低 Nrf2 活性并逆转由此驱动的辐射抵抗这些结果为推进 Nrf2 活性患者的放射增敏策略提供了理论基础。我们通过靶向 PI3K 进行的分析工作也证明了 BRAF 的关键作用，这在遗传上是重要的。我们首次发现，大约 7% 的 NSCLC 患者的肺癌细胞对放射的抵抗力发生了变化。当时，BRAF 激酶结构域突变赋予肺癌对辐射的抵抗力，并且它们与 Nrf2 通路的改变几乎总是肿瘤的次要组成部分（即我们使用的是亚克隆）。数学和实验模型表明克隆结构对这些结果共同提供了令人信服的理由。研究 Nrf2 和 Braf 改变在预测放疗后结果中的作用并推进如果这些假设是正确的，那么针对这些肿瘤患者的基因组引导放射增敏策略。我们的结果将证明放射治疗敏化剂可以根据其特性和类型进行选择（克隆与亚克隆）在患者癌症中发现的基因改变，促进了使用的演变放射治疗从通用方法转变为以个体肿瘤的遗传组成为指导的方法。