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：
10547770
负责人：
Benny Abraham Kaipparettu
金额：
$ 40.85万
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/10547770
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 (BC) 的其他亚型相比，基础或三阴性 (TN) BC 的患病率较差。由于对驱动信号通路的了解有限，因此，对于 TNBC 而言，临床获益。目前可用的靶向疗法有限，迫切需要新的治疗策略。实验室使用的研究流程是利用传输软骨细胞混合（cybrid）模型。优秀的细胞模型，可以比较不同细胞的线粒体（例如：良性细胞和 TNBC 细胞）具有不同的侵袭/转移潜力）在共同定义的核背景中我们应用多个 OMIC。细胞混合模型中发现线粒体核通讯和线粒体能量的方法利用这一研究渠道，我们最近发表了重编程调控的癌症途径。转移性 TNBC 对线粒体脂肪酸 β-氧化 (FAO) 具有高度能量依赖性。我们发现，FAO 是 TNBC 中 Src 肿瘤通路的关键调节因子。我们验证了 cybrid 的研究结果。亲本 BC 细胞模型、PDX 模型和临床数据是最重要的之一。然而，多项临床试验（包括我们自己的试验）中的癌症通路通常上调。结果显示，在未选择的 TNBC 患者中，Src 抑制剂单一药物治疗的临床获益有限。因此，了解TNBC中c-Src的激活和耐药机制对于治疗TNBC具有重要意义。制定可靠的治疗策略来抑制 TNBC 进展。N-肉豆蔻酰化是一种脂质修饰。我们初步将脂肪酸肉豆蔻酸附着到目标蛋白的 N 末端甘氨酸残基上。对细胞杂种模型和亲本细胞的分析表明，FAO 通过增强 c-Src 的肉豆蔻酰化来调节在这个项目中，我们将使用系统验证这一有趣的发现。由于 TNBC 中 Src 抑制剂治疗后频繁出现耐药性，我们我们还分析了TNBC中FAO或Src抑制剂治疗的潜在耐药机制。强有力的初步数据表明，对FAO或Src抑制的耐药性是由于自噬介导的肿瘤存活受活性氧 (ROS) 诱导的 MEK/ERK 通路调节。考虑到我们强大的研究方法，该项目还将验证这一令人兴奋的机制。根据体外和体内初步数据，我们提出了使用多个 PDX 进行大规模临床前研究 TNBC 模型确定联合药物策略的益处，以克服对 FAO 或 Src 的耐药性总体而言，该提案非常重要，因为它有望 1) 揭示线粒体串扰在 TNBC 中 Src 信号传导激活中的重要性，以及 2) 制定策略将现有 FDA 批准的 Src 靶向药物与合适的联合疗法重新用于快速临床翻译以管理当前不可定位的 TNBC。