Validation of OXPHOS gene amplification as a driver of hypoxia and treatment resistance in NSCLC

验证 OXPHOS 基因扩增作为 NSCLC 缺氧和治疗抵抗的驱动因素

基本信息

批准号：
10648605
负责人：
Martin Benej
金额：
$ 7.88万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648605
关键词：
Address Area Automobile Driving Award Cancer Patient Cancer cell line Cell Line Cessation of life Clinical Management Computer Analysis Consumption Data Data Engineering Data Set Diagnosis Disease Dose Engineering Foundations Frequencies Gene Amplification Gene Dosage Genes Genotype Genus Hippocampus Human Hypoxia Immune Immune Targeting Immunotherapy Impairment In Vitro Infiltration Knowledge Luciferases Malignant Neoplasms Malignant neoplasm of lung Measures Messenger RNA Metabolic Methods Mitochondria Modeling Monitor Mus Non-Small-Cell Lung Carcinoma Nuclear Oxidative Phosphorylation Oxygen Oxygen Consumption Prognosis Proliferating Proteins Radiation therapy Recurrent disease Refractory Refractory Disease Reporter Research Role Sampling System T cell infiltration Testing The Cancer Genome Atlas Transgenic Mice Treatment outcome Tumor Oxygenation Tumor Promotion Tumor-infiltrating immune cells United States Validation anticancer treatment cancer therapy clinical translation cytotoxic disorder control experimental analysis image guided immune cell infiltrate immune checkpoint immune checkpoint blockade immune resistance in vivo inhibitor innovation malformation nanoprobe novel novel marker overexpression pharmacologic programmed cell death protein 1 standard of care therapy resistant treatment response tumor tumor growth tumor hypoxia tumor microenvironment validation studies

项目摘要

ABSTRACT Non-small cell lung cancer (NSCLC) is a highly aggressive disease typically diagnosed at locally advanced or metastatic stage, with dismal prognosis associated with high rates of treatment resistance and disease recurrence. Clinical management of NSCLC varies according to the stage. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for localized non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, first line NSCLC treatment has been substantially reinforced with the introduction of immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1), yet long-term disease control occurs in less than 25% of NSCLC patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the dire need of introducing novel synergistic therapies to elicit enhanced treatment response in hypoxic NSCLC tumors. Tumor hypoxia has been associated with anti-cancer treatment resistance for decades, yet its role in clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) PanCancer dataset revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS), and high- level expression of hypoxia-regulated genes (Buffa hypoxia score). Furthermore, we have observed a direct positive correlation between high frequency of copy number amplification (CNA) of several essential OXPHOS genes, and hypoxia levels in NSCLC patient samples. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may be indirectly regulating oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC. The proposed R03 validation study therefore aims to identify the role of high frequency of OXPHOS gene CNA in driving tumor hypoxia and treatment resistance of NSCLC tumors. Upon completion, this study will contribute to current understanding of mechanisms of refractory disease in NSCLC patients and may provide novel markers of treatment outcome.

抽象的非小细胞肺癌（NSCLC）是一种高度侵袭性的疾病，通常在局部晚期或晚期时诊断出来。转移期，预后不佳，治疗耐药率和疾病率高复发。 NSCLC 的临床治疗根据分期的不同而有所不同。高剂量立体定向身体辐射治疗（SBRT）是局部不可切除非小细胞肺癌的标准治疗方法。然而，正如发现的那样六十年前，肿瘤缺氧是有效放射治疗的重大障碍。近十年来，第一线随着针对免疫的免疫疗法的引入，非小细胞肺癌的治疗得到了实质性的加强。诸如程序性细胞死亡 1 (PD-1) 等检查点，但只有不到 25% 的患者能够实现长期疾病控制非小细胞肺癌患者。因此，了解治疗耐药的机制对于解决治疗耐药问题至关重要。迫切需要引入新的协同疗法来增强缺氧 NSCLC 的治疗反应肿瘤。几十年来，肿瘤缺氧一直与抗癌治疗耐药相关，但其在 NSCLC 的临床治疗在很大程度上仍未得到探索。传统上，肿瘤缺氧的基础是归因于畸形的肿瘤脉管系统无法满足氧气供应的高需求快速增殖的肿瘤块。然而，我们对癌症中 NSCLC 患者数据集的初步分析基因组图谱 (TCGA) PanCancer 数据集揭示了高水平表达之间的显着相关性编码氧化磷酸化（OXPHOS）必需的线粒体亚基的核基因，以及高缺氧调节基因的表达水平（Buffa 缺氧评分）。此外，我们还观察到直接几种必需的 OXPHOS 的高拷贝数扩增 (CNA) 频率之间呈正相关 NSCLC 患者样本中的基因和缺氧水平。因为线粒体功能消耗了高达90%的能量可用的细胞氧，其活性可能间接调节肿瘤中的氧可用性通过在将氧气输送到肿瘤后快速消耗氧气来改变微环境。从机制上讲，这导致假设 OXPHOS 基因扩增驱动线粒体功能，进而促进肿瘤发生 NSCLC 中的缺氧和治疗抵抗。因此，拟议的 R03 验证研究旨在确定 OXPHOS基因CNA高频率驱动肿瘤缺氧及NSCLC治疗耐药的作用肿瘤。完成后，这项研究将有助于当前对难治性疾病机制的理解 NSCLC 患者中，可能提供治疗结果的新标志物。