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:
- 金额:$ 34.69万
- 依托单位:
- 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:
- 关键词:BiologicalBiological AssayBiological SciencesCD36 geneCancer EtiologyCancer PatientCause of DeathCecumCell SurvivalCessation of lifeClinicalCollaborationsColorectal CancerDataDevelopmentDiseaseDrug EvaluationDrug TargetingEnvironmentEnzymesFatty AcidsFatty-acid synthaseGoalsGrowthHumanIn VitroIncidenceInjectionsKnowledgeLipidsLiteratureMalignant NeoplasmsMediatingMetabolicMetabolic PathwayMetabolismMetastatic Neoplasm to the LiverMetastatic Neoplasm to the LungMetastatic toMicroarray AnalysisModelingMolecularMorbidity - disease rateMusNeoplasm MetastasisOncologyOrganOrganoidsOutcomePalmitatesPathway interactionsPatientsPharmacologyPhase I/II Clinical TrialPhase II Clinical TrialsPre-Clinical ModelPrognosisPublic HealthRecurrenceRegulationResearchRoleSamplingSignal PathwaySolidSolid NeoplasmSpecimenSphingolipidsSphingosineTestingTherapeuticTissue MicroarrayTumor AngiogenesisUnited StatesUp-RegulationValidationWomananalogantibody inhibitorbasecancer cellcolorectal cancer metastasiscolorectal cancer progressiondisorder riskfatty acid metabolismgenetic approachhigh riskin vivoin vivo Modelinhibitorlipid biosynthesislipid metabolismmenmetabolomicsmortalitymouse modelneutralizing antibodynew therapeutic targetnovelnovel therapeutic interventionoverexpressionpatient derived xenograft modelpreclinical studypreventresistance mechanismresponsesphingosine 1-phosphatesphingosine kinasestable isotopetargeted treatmenttherapeutic targettranscriptome sequencingtranslational impacttranslocasetumortumor metabolismuptake
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.
项目总结
转移是包括结直肠癌(CRC)在内的实体瘤的主要死亡原因。我们的长期目标是开发更具选择性的治疗方案,通过了解脂肪酸代谢的变化如何促进转移性疾病来预防或减少结直肠癌转移的发生率。
脂肪酸合酶(FASN)是结直肠癌脂肪合成的关键酶,在结直肠癌中显著上调和激活,其活性与预后不良、复发和死亡风险高有关。我们确定FASN是晚期结直肠癌的潜在靶点,并表明该酶的上调是支持结直肠癌转移的关键机制。然而,FASN调控转移的潜在机制和抵抗FASN抑制的潜在机制尚不清楚。目前的应用提出了一个全面的研究计划,以研究通过脂代谢调节结直肠癌转移的新机制。我们的初步数据表明,从头合成脂肪酸的主要产物棕榈酸酯被选择性地用于鞘磷脂的合成。FASN的过表达选择性地调节SphK1和SphK2的活性,并增加鞘氨醇-1-磷酸(S1P)的水平,S1P是一种与转移有关的生物活性鞘磷脂。因此,在目标1中,我们将验证FASN通过上调SphK/S1P轴促进转移的假设,并确定SphK1和SphK2在结直肠癌转移中的作用。此外,我们的初步研究表明,FASN和CD36的表达之间存在相关性,CD36是一种负责外源FA摄取的脂肪酸转移酶。我们的数据显示,抑制FASN导致CD36上调,这可能是目前正在进行第二阶段临床试验的新型FASN抑制剂耐药的潜在机制。因此,在目标2中,我们将阐明FASN如何调控CD36,并确定CD36上调促进结直肠癌转移的分子机制,包括CD36上调对鞘磷脂代谢和S1P合成的影响。在目标3中,我们将测试通过CD36抑制FA摄取是否会增加新型FASN抑制剂TVB-3664对结直肠癌的疗效。
我们将利用来自患者的生物样本、人类原代结直肠癌细胞、从转基因小鼠建立的肿瘤有机物和结直肠癌转移模型,这是临床前靶点和药物评估的最先进模型。这些模型将与最先进的方法结合使用,包括靶向和稳定的同位素分解代谢组学(SIRM),以评估脂质合成和FA摄取变化对癌细胞代谢的影响。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期临床试验中进行测试,迫切需要更多关于它们在结直肠癌中的作用的研究和知识。除了确认FASN、SphKs和CD36作为结直肠癌的治疗靶点外,当前应用中提出的对代谢和信号通路的综合分析也有可能发现新的可用药靶点和结直肠癌治疗策略。
项目成果
期刊论文数量(0)
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YEKATERINA ZAYTSEVA其他文献
YEKATERINA ZAYTSEVA的其他文献
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{{ truncateString('YEKATERINA ZAYTSEVA', 18)}}的其他基金
Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer
脂肪酸合酶在结直肠癌中调节 UDP-GlcNAc 合成
- 批准号:
10437880 - 财政年份:2021
- 资助金额:
$ 34.69万 - 项目类别:
Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer
脂肪酸合酶在结直肠癌中调节 UDP-GlcNAc 合成
- 批准号:
10287757 - 财政年份:2021
- 资助金额:
$ 34.69万 - 项目类别:
Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk
超级基金化学品、营养和多器官心血管风险
- 批准号:
10596286 - 财政年份:1997
- 资助金额:
$ 34.69万 - 项目类别:
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