Targeting Lipid Metabolism in Colorectal Cancer

靶向结直肠癌的脂质代谢

基本信息

批准号：
10374051
负责人：
YEKATERINA ZAYTSEVA
金额：
$ 34.69万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374051
关键词：
Biological Biological Assay Biological Sciences CD36 gene Cancer Etiology Cancer Patient Cause of Death Cecum Cell Survival Cessation of life Clinical Collaborations Colorectal Cancer Data Development Disease Drug Evaluation Drug Targeting Environment Enzymes Fatty Acids Fatty-acid synthase Goals Growth Human In Vitro Incidence Injections Knowledge Lipids Literature Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Metastatic to Microarray Analysis Modeling Molecular Morbidity - disease rate Mus Neoplasm Metastasis Oncology Organ Organoids Outcome Palmitates Pathway interactions Patients Pharmacology Phase I/II Clinical Trial Phase II Clinical Trials Pre-Clinical Model Prognosis Public Health Recurrence Regulation Research Role Sampling Signal Pathway Solid Solid Neoplasm Specimen Sphingolipids Sphingosine Testing Therapeutic Tissue Microarray Tumor Angiogenesis United States Up-Regulation Validation Woman analog antibody inhibitor base cancer cell colorectal cancer metastasis colorectal cancer progression disorder risk fatty acid metabolism genetic approach high risk in vivo in vivo Model inhibitor lipid biosynthesis lipid metabolism men metabolomics mortality mouse model neutralizing antibody new therapeutic target novel novel therapeutic intervention overexpression patient derived xenograft model preclinical study prevent resistance mechanism response sphingosine 1-phosphate sphingosine kinase stable isotope targeted treatment therapeutic target transcriptome sequencing translational impact translocase tumor tumor metabolism uptake

项目摘要

PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated and activated in CRC, and its activity is associated with poor prognosis, higher risk of disease recurrence, and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However, the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis, palmitate, is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P), a bioactive sphingolipid implicated in metastasis. Therefore, in Aim 1, we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore, our preliminary studies show a correlation between expression of FASN and CD36, a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore, in Aim 2, we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3, we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients, human primary CRC cells, tumor organoids established from genetically modified mice and CRC metastasis models, which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches, including targeted and stable isotope-resolved metabolomics (SIRM), to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN, SphKs and CD36 as therapeutic targets in CRC, the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.

项目摘要转移是包括结直肠癌（CRC）在内的实体瘤死亡的主要原因。我们的长期目标是通过了解脂肪酸代谢的变化如何导致转移性疾病的变化来开发更有选择性的治疗选择，以防止或减少CRC转移的发生率。脂肪酸合酶（FASN）是从头脂质合成的关键酶，在CRC中显着上调和激活，其活性与预后不良，疾病复发的较高风险和死亡有关。我们将FASN确定为晚期CRC的潜在靶标，并表明该酶的上调是支持CRC转移的关键机制。然而，尚不清楚FASN调节的基本机制和对FASN抑制的潜在机制。当前的应用提出了一项全面的研究计划，以研究脂质代谢调节CRC转移的新机制。我们的初步数据表明，从头脂肪酸合成棕榈酸酯的主要产物被选择地用于鞘脂合成。 FASN的过表达选择性调节SPHK1和SPHK2的活性，并增加了鞘氨酸-1-磷酸盐（S1P）的水平，这是一种与转移有关的生物活性鞘脂。因此，在AIM 1中，我们将测试以下假设：FASN通过上调SPHK/S1P轴增强转移，并确定SPHK1和SPHK2对CRC转移的贡献。此外，我们的初步研究表明，FASN和CD36的表达是一种负责外源性FA摄取的脂肪酸易位酶。我们的数据表明，FASN的抑制会导致CD36的上调，这可能是对当前在II期临床试验中正在测试的新型FASN抑制剂的耐药机制。因此，在AIM 2中，我们将阐明FASN如何调节CD36并确定CD36上调有助于CRC转移的分子机制，包括CD36上调对鞘脂代谢和S1P合成的影响。在AIM 3中，我们将测试是否通过CD36抑制FA摄取是否会提高CRC中新型FASN抑制剂TVB-3664的功效。我们将利用来自患者，人类原发性CRC细胞，基因改良小鼠和CRC转移模型建立的生物样品，这是用于临床前靶标和药物评估的最先进的模型。这些模型将与最新方法一起使用，包括靶向和稳定的同位素分辨代谢组学（SIRM），以评估脂质合成和FA摄取对癌细胞代谢的影响的影响。这些研究具有很高的翻译影响，因为CD36和FASN抑制剂目前在多个临床前研究和I-II期临床试验中进行了测试，并且迫切需要对其在CRC中的影响进行更多的研究和知识。除了验证FASN，SPHK和CD36作为CRC的治疗靶标外，对当前应用中提出的代谢和信号通路的全面分析也有可能确定CRC的新型可药物目标和治疗策略。