Energy reprogramming-regulated oncopathways and drug resistance in triple negative breast cancer

三阴性乳腺癌中能量重编程调节的肿瘤途径和耐药性

基本信息

批准号：
10738335
负责人：
Benny Abraham Kaipparettu
金额：
$ 6.33万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10738335
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Aftercare Autophagocytosis Benign Binding Bioinformatics Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Carrier Proteins Cell model Cells Characteristics Citrates Citric Acid Cycle Clinical Clinical Data Clinical Trials Coenzyme A Combined Modality Therapy Communication Cytoplasm Dasatinib Data Dependence Drug Combinations Drug Targeting Drug resistance Enzymes FDA approved Fatty Acids Generations Glycine Glycolysis Goals In Vitro Invaded Lipids MEKs Malignant Neoplasms Mechanics Mediating Membrane Messenger RNA Mitochondria Modeling Modification Myristates Myristic Acylation Site N-Myristoylation N-myristoyltransferase N-terminal NMT2 gene Neoplasm Metastasis Nuclear Oncogenic Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Phase II Clinical Trials Phase Ib/II Trial Phosphotransferases Population Primary Neoplasm Prognosis Property Proteins Publishing Reactive Oxygen Species Recurrence Regulation Reporting Research Resistance Role SRC gene Severities Signal Pathway Signal Transduction System Testing The Cancer Genome Atlas Therapeutic Tissues breast cancer progression cancer subtypes citrate carrier clinical translation drug resistance development hormone receptor-negative hormone receptor-positive in vivo inhibitor inhibitor therapy mRNA Expression malignant breast neoplasm metabolomics multiple omics myristoylation novel novel therapeutic intervention oxidation palmitoylation patient derived xenograft model preclinical study resistance mechanism response src-Family Kinases targeted treatment translational approach translational potential treatment strategy triple-negative invasive breast carcinoma tumor

项目摘要

Abstract: Compared to other subtypes of breast cancers (BC), basal or triple negative (TN) BC suffers a poor prognosis, caused by limited understanding of the driver signaling pathways. Thus, for TNBC, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. PI's lab uses a research pipeline that utilizes transmitochondrial cybrid (cybrid) models. Cybrid system is an excellent cell model that allows comparing mitochondria from different cells (example: benign and TNBC cells with varying invasion/metastatic potential) in a common defined nuclear background. We apply multiple OMICs approaches in cybrid models to discover mitochondria-nuclear communication and mitochondrial energy reprogramming regulated cancer pathways. Using this research pipeline, we have recently published that metastatic TNBC has high energy-dependence to mitochondrial fatty acid β-oxidation (FAO). We have also discovered that FAO is a critical regulator of Src oncopathway in TNBC. We validated the findings from cybrid models in parental BC cells, PDX models and clinical data. Proto-oncogene c-Src is one of the most commonly upregulated cancer pathways in TNBC. However, multiple clinical trials including our own trial showed only limited clinical benefit with single drug approach of Src inhibitors in unselected TNBC patients. Thus, it is important to understand the mechanism of activation and drug resistance of c-Src in TNBC to develop reliable treatment strategies to inhibit TNBC progression. N-myristoylation is a lipid modification with the attachment of a fatty acid, myristate, onto the N- terminal glycine residue of target proteins. Our preliminary analysis in cybrid models and parental cells suggest that FAO regulates myristoylation of c-Src by enhancing cytosolic availability of myristoyl CoA. In this project we will validate this interesting finding using systematic modulation of FAO pathway. Since frequent drug resistance occurs after Src inhibitor therapy in TNBC, we have also analyzed the potential drug resistance mechanisms for FAO or Src inhibitor therapy in TNBC. Our strong preliminary data suggest that drug resistance to FAO or Src inhibition is due to autophagy-mediated tumor survival that is regulated by the reactive oxygen species (ROS)-induced MEK/ERK pathway. Thus, this project will also validate this exciting mechanism using multiple research approaches. Considering our strong in vitro and in vivo preliminary data, we have proposed large-scale preclinical studies using multiple PDX TNBC models to determine benefit of combination drug strategy to overcome the resistance to FAO or Src inhibition therapy in TNBC. Overall, this proposal is highly significant as it is expected to 1) reveal the significance of mitochondrial crosstalk in the activation of Src signaling in TNBC and 2) develop strategies to repurpose the existing FDA approved Src targeting drugs with suitable combination therapy for rapid clinical translation to manage currently non-targetable TNBC.

摘要：与乳腺癌的其他亚型（BC）相比，基底或三重阴性（TN）BC遭受较差预后是由于对驾驶员信号通路的有限理解而引起的。对于TNBC而言，临床益处从目前可用的靶向疗法中，迫切需要新的治疗策略。 pi LAB使用利用多蒙蒙膜软骨细胞抗三（CYBRID）模型的研究管道。 Cybrid系统是优秀的细胞模型，可以比较来自不同细胞的线粒体（例如：良性和TNBC细胞在常见的核背景下，具有不同的入侵/转移潜力）。我们应用多个OMICS 圆柱模型中的方法，发现线粒体 - 核通信和线粒体能量重编程调节的癌症途径。使用此研究管道，我们最近发表了转移性TNBC对线粒体脂肪酸β-氧化（FAO）具有很高的能量依赖性。我们也有发现粮农组织是TNBC中SRC OnCopathway的关键调节剂。我们验证了Cybrid的发现父母BC细胞，PDX模型和临床数据中的模型。原始癌基因C-SRC是最多的 TNBC中通常上调的癌症途径。但是，包括我们自己的试验在内的多个临床试验在未选择的TNBC患者中，SRC抑制剂的单一药物方法仅显示有限的临床益处。这是重要的是要了解C-SRC在TNBC中的激活和耐药性机理制定可靠的治疗策略来抑制TNBC的进展。 N- myristoylation是一种脂质修饰脂肪酸（肉豆蔻酸酯）附着在靶蛋白的N末端甘氨酸保留量上。我们的初步圆柱模型和父母细胞中的分析表明，FAO通过增强C-SRC的肉豆蔻酰化。 Myristoyl COA的胞质可用性。在这个项目中，我们将使用系统性验证这一有趣的发现 FAO途径的调节。由于在TNBC中SRC抑制剂治疗后经常发生耐药性，我们还分析了TNBC中粮农组织或SRC抑制剂治疗的潜在耐药性机制。我们的强的初步数据表明，对粮农组织或SRC抑制的耐药性是由于自噬介导的由活性氧（ROS）诱导的MEK/ERK途径调节的肿瘤存活率。那，这个项目还将使用多种研究方法来验证这种令人兴奋的机制。考虑到我们的坚强在体外和体内初步数据，我们提出了使用多个PDX的大规模临床前研究 TNBC模型确定组合药物策略的好处以克服对粮农组织或SRC的抗性 TNBC抑制疗法。总体而言，该提议非常重要，因为预计1）揭示线粒体串扰在TNBC中SRC信号激活中的重要性和2）开发策略重新利用现有的FDA批准的SRC靶向药物，并使用合适的联合疗法快速临床翻译以管理当前不可靶向的TNBC。