Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity

代谢适应使顺铂耐药并抑制肿瘤免疫

基本信息

批准号：
10518177
负责人：
VLAD C SANDULACHE
金额：
$ 30.6万
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：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518177
关键词：
Ablation Aggressive behavior Amino Acids Anabolism Automobile Driving Biological Markers Carbon Catabolism Cell Line Cells Chemicals Cisplatin Clinic Clinical Coupled Data Development Effectiveness Enzymes Equilibrium FADH2 Generations Genetic Transcription Genomics Genotoxic Stress Glucose Glutamine Glutathione Head and Neck Squamous Cell Carcinoma Human Image Immune Immune checkpoint inhibitor Immunocompetent Immunologic Surveillance Immunologics In Vitro Incidence Individual Light Link Lung Malignant Neoplasms Measurement Measures Mediating Metabolic Metabolism Mitochondria Modeling Molecular Target Myeloid-derived suppressor cells NF-kappa B Natural regeneration Paracrine Communication Pathway interactions Patients Peroxidases Peroxides Phenotype Platinum Platinum Compounds Population Pre-Clinical Model Production Prostaglandin Production Prostaglandins Research Resistance Resistance development Role Signal Transduction Solid Neoplasm Stress Testing Time Treatment Failure Tumor Immunity Tumor-Infiltrating Lymphocytes Work amino acid metabolism base cancer type chemokine chemotherapy cytokine cytotoxic defined contribution design disorder control experimental study immunoregulation in vivo knock-down mouse model neoplastic cell overexpression patient biomarkers patient response personalized approach response small hairpin RNA therapy resistant treatment response tumor tumor behavior tumor growth tumor-immune system interactions

项目摘要

Project 1 SUMMARY A clearer understanding of how tumor cells survive the stress of platinum agents and evolve into therapy resistant populations is essential to overcome treatment failure and maximize both disease control and survival. Our data demonstrate that HNSCC cell lines with acquired cisplatin resistance reduce glycolytic and mitochondrial energy production while increasing carbon flux into anabolic pathways. This results in an enhanced reductive potential (glutathione, NAD(P)H, FADH2) via both glucose and glutamine catabolism coupled to increased glutathione (GS) peroxidase 2 (GPX2) activity coordinated at a genomic and transcriptional level, partially through the KEAP1-NRF2 pathway. Hyperactivation of GPX2 concomitantly likely inhibits NF-κB activation, decreasing chemokine and prostaglandin production by tumor cells— leading to a suppressive tumor immune microenvironment (TIME) enriched for myeloid derived suppressor cells (MDSCs) and depleted of cytotoxic tumor infiltrating lymphocytes (TILs). It is our central hypothesis that this metabolic adaptation is a permissive and required step for acquisition of cisplatin resistance. We further postulate that this metabolic shift transitions some tumors to an immunologically silent phenotype, which reduces immune surveillance to compound the aggressive behavior and cross-therapy resistance of CDDP-treated tumors We will first define the critical metabolic steps required for generation of an enhanced reductive state that supports cisplatin resistance in Aim 1. We will utilize in vitro and in vivo orthotopic HNSCC models to measure the contribution of glucose and glutamine to GS synthesis in cisplatin resistant tumors and, using chemical inhibition coupled to shRNA blockade of individual transporters and enzymes, identify the critical rate limiting metabolic steps for GS synthesis and cisplatin resistance in HNSCC. In Aim 2 we will determine how GS synthesis and utilization (by GPX2 and non GPX means) are coordinated transcriptionally at least in part through Nrf2 in order to support cisplatin resistance. In Aim 3 we will test the impact of GS metabolism via canonical (e.g. NF-kB) and metabolic paracrine signaling on development of a suppressive TIME. Completion of the proposed experiments will: 1) identify suitable targets for ablation of the enhanced reductive state driving cisplatin resistance in HNSCC and 2) identify metabolic biomarkers which can be coupled to 13C flux imaging-based measurements to generate real-time readout of tumor treatment response, and inform a more personalized approach to targeting metabolism to overcome CDDP resistance. By identifying the critical mechanistic underpinnings of metabolic adaptation, we can generate a paradigm shift in our capability to both rapidly detect acquisition of resistance to genotoxic stress and to overcome it using multiple clinically viable approaches. It will further shed light on how acquisition of cisplatin resistance can impact response to immunomodulatory approaches such as immune checkpoint inhibitors (ICIs) currently being combined with chemotherapy in the clinic.

项目1摘要对肿瘤细胞如何在铂剂的应力下生存并演变为抗治疗群体对于克服治疗衰竭和最大化疾病控制和最大化至关重要生存。我们的数据表明，具有获得顺铂耐药性的HNSCC细胞系减少了糖酵解和线粒体能量产生，同时将碳通量增加到合成代谢途径。这导致通过葡萄糖和谷氨酰胺分解代谢增强了降低电势（谷胱甘肽，NAD（P）H，FADH2）结合在基因组和转录水平，部分通过KEAP1-NRF2途径。 GPX2的过度激活可能抑制NF-κB激活，降低肿瘤细胞的趋化因子和前列腺素的产生 - 领先富含粒细胞衍生的抑制细胞的抑制性肿瘤免疫微环境（时间）（MDSC）并耗尽了细胞毒性肿瘤浸润淋巴细胞（TILS）。我们的中心假设是代谢适应是获得顺铂耐药性的允许和所需步骤。我们进一步假设，这种代谢转移过渡到某些肿瘤向免疫学上沉默的表型，这降低了免疫监视以使侵略性行为和抗药性的抗性 CDDP处理的肿瘤我们将首先定义生成增强状态所需的关键代谢步骤这支持AIM 1中的顺铂耐药性。我们将在体外和体内原位HNSCC模型中使用测量谷氨酰胺和谷氨酰胺对顺铂耐药性肿瘤中GS合成的贡献，并使用化学抑制作用耦合到shRNA的单个转运蛋白和酶的阻滞，鉴定关键 HNSCC中GS合成和顺铂抗性的代谢步骤的速率限制。在目标2中，我们将确定GS的合成和利用方式（通过GPX2和非GPX均值）是协调的转录至少部分通过NRF2来支持顺铂耐药。在AIM 3中，我们将测试GS的影响通过规范（例如NF-KB）和代谢旁分泌信号传导的代谢时间。提议的实验的完成将：1）确定烧蚀的合适目标在HNSCC中驱动顺铂耐药性的降低降低，2）识别可以使用的代谢生物标志物将基于13C磁通成像的测量耦合，以产生肿瘤治疗的实时读数响应，并告知一种更个性化的方法来靶向代谢以克服CDDP抗性。通过确定代谢适应的关键机理基础，我们可以生成范式转移我们的能力，既可以快速检测到对遗传毒性应激的抗性的获取并克服它使用多种临床可行的方法。它将进一步阐明如何获得顺铂耐药性会影响对免疫调节方法（例如免疫切除剂抑制剂）的反应（ICI）目前与诊所的化学疗法结合使用。