Targeting the metabolic vulnerabilities of patient-derived drug resistant tumors

针对患者来源的耐药肿瘤的代谢脆弱性

基本信息

批准号：
10311106
负责人：
MARIA L AVANTAGGIATI
金额：
$ 17.87万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-02 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311106
关键词：
Acids Address Antiviral Response Cell Nucleus Cell Respiration Cells Characteristics Cisplatin Citrates Clinical Management Cytoplasm Cytosol Data Dependence Development Disease Drug resistance Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Evolution Gene Chips Gene Expression Genetic Growth Immune response In Vitro Innate Immune Response Interferon Type I Interferons Knowledge Laboratories Left Link Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Methods Mind Mitochondria Mitochondrial DNA Mutation Non-Small-Cell Lung Carcinoma Nucleic Acids Oncogenes Organoids Output Oxidative Phosphorylation Oxidative Stress Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Platinum Play Population Primary Neoplasm Proliferating Radiation Relapse Resistance Role Signal Transduction System Testing Therapeutic Therapeutic Agents Tumor-Derived Viral antitumor agent base cancer cell cancer initiation cancer stem cell citrate carrier clinical application conventional therapy driver mutation exome sequencing in vivo inhibitor lung cancer cell mitochondrial metabolism neoplastic cell novel novel therapeutics response self-renewal sensor stem stem-like cell stemness therapy development therapy resistant tool trait tumor tumor initiation

项目摘要

Project Summary Advanced NSCLC still remains an incurable disease, at least in part due to resilient populations of stem-like, cancer initiating cells (CSCs) that survive conventional therapies and reignite post-therapy relapse and metastatic dissemination. This proposal will test the hypothesis that the mitochondrial citrate carrier, Slc25a1, acts as a key metabolic hub through which NSCLC acquire resistance to different therapeutic agents. Given that the genetic spectrum of mutations continues to evolve during the course of therapy, newly emerging mutations may not always be targetable with currently available drugs. Thus, the development of therapies that act regardless of the mutational profile of tumors is an attractive concept. We have recently shown that Slc25a1 promotes CSC expansion and self-renewal, enhancing the energetic output of this population by promoting the mitochondrial entry of citrate with consequent induction of mitochondrial metabolism and oxidative phosphorylation. The scope of the current project is to identify the metabolic hallmarks of drug resistance in patient-derived tumors. Our preliminary data show that resistance to inhibitors of the Epidermal Growth Factor Receptor, EGFR or to platinum therapy involves a switch- and a dependency- towards Slc25a1-driven mitochondrial metabolism accompanied by the induction of a stemness phenotype. Hence, CTPI-2 is synthetic lethal with cisplatin or with EGFR inhibitor co-treatment and restores sensitivity to these agents in vitro and in vivo. Further, we provide evidence that Slc25a1 induces an Interferon type I (IFN-I) anti-viral innate immune response, likely driven by oxidative stress and by accumulation of mitochondrial DNA (mtDNA) in the cytoplasm. We link this signature to the therapy resistance phenotype induced by Slc25a1. With this in mind, the scopes of the current project are to test the hypothesis that Slc25a1 allows drug-resistant cells to endure and survive therapeutic attacks in an energetically favorable state and that tumors resistant to different types of drugs rely upon common metabolic traits driven by Slc25a1. Second, we will clarify whether IFN-I is involved in the drug resistant phenotype driven by Slc25a1. In Aim 1 we will use a newly developed organoid system that allows for the expansion of primary tumors derived from patients to determine whether Slc25a1 drives different types of drug resistance independently of the primary driver mutations. In Aim 2 we will determine whether components of the newly identified Slc25a1-mtDNA-IFN-I loop are responsible for induction of the stemness phenotype and the insensitivity to drugs that act predominantly on highly proliferating cells. Together, these studies will provide a major advance in enlightening novel mechanisms underlying NSCLC pathogenesis, will fill a gap in knowledge elucidating unexpected mechanistic links between the mitochondria, stemness and drug-resistance, which we will ultimately hope will open new therapeutic opportunities for the treatment of this deadly disease.

项目概要晚期非小细胞肺癌仍然是一种无法治愈的疾病，至少部分归因于具有弹性的干细胞群，癌症起始细胞（CSC）能够在传统疗法中存活并重新引发治疗后复发，转移性播散。该提案将检验线粒体柠檬酸载体 Slc25a1 的假设，作为关键的代谢中心，非小细胞肺癌通过它获得对不同治疗药物的耐药性。鉴于突变的遗传谱在治疗过程中不断演变，新出现的突变目前可用的药物可能并不总是能够靶向。因此，开发有效的疗法无论肿瘤的突变谱如何，都是一个有吸引力的概念。我们最近证明了 Slc25a1 促进 CSC 扩张和自我更新，通过促进柠檬酸盐进入线粒体，随后诱导线粒体代谢和氧化磷酸化。当前项目的范围是确定耐药性的代谢特征患者来源的肿瘤。我们的初步数据表明，对表皮生长因子抑制剂的耐药性受体、EGFR 或铂疗法涉及对 Slc25a1 驱动的转换和依赖性线粒体代谢伴随着干性表型的诱导。因此，CTPI-2 是合成的与顺铂或 EGFR 抑制剂联合治疗可致死，并在体外和体内恢复对这些药物的敏感性体内。此外，我们提供的证据表明 Slc25a1 诱导 I 型干扰素 (IFN-I) 抗病毒先天免疫反应，可能是由氧化应激和细胞质中线粒体 DNA (mtDNA) 的积累驱动的。我们将此特征与 Slc25a1 诱导的治疗耐药表型联系起来。考虑到这一点，范围当前的项目是测试 Slc25a1 允许耐药细胞耐受和存活的假设治疗攻击处于有利的能量状态，并且肿瘤对不同类型药物的耐药性依赖于基于 Slc25a1 驱动的常见代谢特征。其次，我们要明确该药物是否涉及IFN-I 由 Slc25a1 驱动的耐药表型。在目标 1 中，我们将使用新开发的类器官系统，该系统可以扩展源自患者的原发肿瘤以确定 Slc25a1 是否驱动不同类型的耐药性独立于主要驱动突变。在目标 2 中，我们将确定组件是否新鉴定的 Slc25a1-mtDNA-IFN-I 环负责诱导干性表型和对主要作用于高度增殖细胞的药物不敏感。这些研究将共同提供 NSCLC发病机制的启发性新机制的重大进展将填补知识空白阐明线粒体、干性和耐药性之间意想不到的机制联系，我们最终希望能为治疗这种致命疾病开辟新的治疗机会。