Targeting tumor cell macrophage lipid interactions to overcome resistance to androgen receptor targeted therapy

靶向肿瘤细胞巨噬细胞脂质相互作用以克服对雄激素受体靶向治疗的耐药性

基本信息

批准号：
10651105
负责人：
Asmaa Elkenawi
金额：
$ 42.31万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651105
关键词：
27-hydroxycholesterol Address Adopted Anabolism Androgen Receptor Androgens Antitumor Response Automobile Driving Binding Biological Assay Biological Markers Cancer Patient Cell Communication Cell Line Cell Proliferation Cells Cholesterol Cholesterol Homeostasis Clinical Clinical Data Coculture Techniques DNA Sequence Alteration Data Disease Drug resistance Equilibrium Family Generations Genes Genetic Transcription Goals Immune Immunocompetent Immunocompromised Host Immunofluorescence Immunologic In Vitro Infiltration Ions Iron LXRalpha protein Lipids Liver X Receptor Macrophage Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Mediator Metabolic Metabolism Metals Molecular Profiling Nuclear Receptors Patients Phenotype Population Production Promoter Regions Prostatic Neoplasms RNA Receptor Activation Receptor Signaling Reporting Resistance Role Sampling Steroid biosynthesis System Therapeutic Therapeutic Intervention Tumor-associated macrophages Validation Work advanced disease androgen deprivation therapy antagonist anticancer research cancer cell castration resistant prostate cancer cholesterol biosynthesis chromatin immunoprecipitation cytokine enzalutamide extracellular improved in vivo inhibitor loss of function metabolomics mouse model neoplastic cell novel prospective prostate cancer cell prostate cancer progression resistance mechanism response six transmembrane epithelial antigen of the prostate 4 targeted treatment therapy resistant transcription factor transcriptomics tumor tumor microenvironment

项目摘要

Abstract Tumor-associated macrophages are key effector immune cells that promote prostate cancer progression. Studies in other cancers show that macrophage secrete cytokines, angiogenic mediators and/or metabolites to drive resistance to various therapeutics. Here we sought to determine the role of macrophage altered metabolism in driving resistance to androgen receptor (AR) targeted therapy. Unbiased transcriptomic analysis of prostate tumors following macrophage depletion revealed that macrophage infiltration was associated with molecular signatures of AR activation and cholesterol transport. These findings were recapitulated in vitro, with the co- culture of macrophages and prostate cancer cells enhancing AR nuclear localization, increasing cancer cell proliferation in androgen-deprived conditions, and reducing sensitivity to the AR antagonist, enzalutamide. We then characterized role of cholesterol in macrophage tumor cell lipid interaction and AR activation and identified the transcriptional regulator of cholesterol metabolism LXR as a novel mediator of macrophage-induced AR activation. Accordingly, we hypothesize that altered macrophage metabolism in prostate cancer drives resistance to AR-targeted therapy via LXR dependent perturbation of cholesterol transport and biosynthesis. The cholesterol exchange may be further propelled by metal ion availability in tumor microenvironment as our new findings suggested. To address this, we propose to 1) Determine the mechanisms by which macrophages drive resistance to androgen receptor targeted therapy. 2) To evaluate the therapeutic potential of targeting macrophage-tumor cell lipid interactions to overcome resistance to AR inhibitors. The goal of this project is to identify metabolic liabilities in tumor microenvironment that can be targeted to achieve cure in prostate cancer patients.

抽象的肿瘤相关的巨噬细胞是促进前列腺癌进展的关键效应免疫细胞。其他癌症的研究表明，巨噬细胞分泌细胞因子，血管生成介质和/或代谢物动力抗各种治疗剂。在这里，我们试图确定巨噬细胞改变新陈代谢的作用在推动对雄激素受体（AR）靶向治疗的抗性方面。前列腺的公正转录组分析巨噬细胞耗竭后的肿瘤表明巨噬细胞浸润与分子有关 AR激活和胆固醇运输的特征。这些发现在体外概括了，共同巨噬细胞和前列腺癌细胞的培养增强了AR核定位，增加了癌细胞雄激素剥夺条件的增殖，并降低对AR拮抗剂Enzalutamide的敏感性。我们然后表征胆固醇在巨噬细胞肿瘤细胞脂质相互作用和AR激活中的作用，并确定胆固醇代谢LXR的转录调节剂是巨噬细胞诱导的AR的新型介体激活。因此，我们假设改变前列腺癌的巨噬细胞代谢会驱动抗药性通过LXR依赖于胆固醇转运和生物合成的靶向AR靶向治疗。这肿瘤微环境中的金属离子可用性可能会进一步推动胆固醇的交换提出的发现。为了解决这个问题，我们建议1）确定巨噬细胞驱动的机制对雄激素受体靶向治疗的抗性。 2）评估靶向的治疗潜力巨噬细胞肿瘤细胞脂质相互作用以克服对AR抑制剂的抗性。这个项目的目标是确定可以针对前列腺癌治愈的肿瘤微环境中的代谢负债患者。