Ceramide NanoLiposomes as a novel therapeutic for prostate cancer

神经酰胺纳米脂质体作为前列腺癌的新型治疗方法

基本信息

批准号：
10015250
负责人：
Pedro Filipe Da Costa Pinheiro
金额：
$ 3.4万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2019-09-10 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015250
关键词：
Ablation Acetates Agonist Anabolism Androgen Antagonists Androgen Metabolism Androgen Receptor Androgens Animals Area Award Big Data Binding Biology Cancer Patient Cell Death Cell Line Cells Ceramides Cessation of life ChIP-seq Data Development Differentiation and Growth Dihydrosphingosine Disease Disease Progression Drug Targeting Enzymes Epigenetic Process Evaluation FDA approved Future Generations Genetic Transcription Gland Goals Grant Growth and Development function Hormonal Hormone Responsive Hormones Knockout Mice Knowledge LNCaP Laboratories Laboratory Research Link Lipids Liposomes Malignant Neoplasms Malignant neoplasm of prostate Measures Messenger RNA Metabolism Modality Modeling Molecular Newly Diagnosed Nuclear Hormone Receptors PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Play Population Postdoctoral Fellow Pre-Clinical Model Prostate Proteins Publishing Receptor Signaling Regulation Research Research Personnel Research Project Grants Role Second Messenger Systems Signal Pathway Sphingolipids Testosterone Therapeutic Transcriptional Regulation Treatment Efficacy Tumor Burden Work Xenograft procedure abiraterone advanced prostate cancer androgen deprivation therapy anti-cancer therapeutic base bioinformatics tool bisulfite sequencing cancer cell cancer diagnosis career castration resistant prostate cancer chromatin immunoprecipitation epigenome field study hormone therapy improved in vitro Model lipid metabolism male men mouse model nanoliposome new therapeutic target novel novel therapeutics organ growth promoter prostate cancer cell prostate cancer model receptor binding relapse patients targeted treatment therapeutic target transcriptome sequencing tumor tumor progression tumorigenesis virtual whole genome

项目摘要

Project Summary/Abstract Prostate cancer (PCa) is the second most incident cancer in men worldwide and despite vast amounts of research, treatment of this disease remains elusive. The prostate is regulated by male hormones (e.g. testosterone) that activate the androgen receptor (AR) to trigger signaling pathways involved in the organ’s development and growth. In PCa, these hormones exert an important role in the onset and progression of the disease, and therefore have been the main therapeutic target for PCa patients. However, virtually all patients relapse and develop Castration-Resistant PCa (CRPC), the lethal stage of the disease. Therefore novel and more efficacious therapeutics are extremely important for PCa patients. In the F99-phase of this project, the potential of sphingolipid-based therapeutics for PCa will be examined. Ceramide nanoliposomes (CNL) are extremely efficacious in causing cell death of aggressive in vitro models of PCa, and these liposomes have a therapeutic potential also when combined with FDA-approved drugs that target the AR signaling axis. The working hypothesis is that AR regulates sphingolipid metabolism hindering the efficacy of CNL in PCa. To investigate the relationship between the androgen receptor and ceramide metabolism, we will specifically study (1) the mechanism’s by which AR regulates ceramide metabolism and how this impacts the efficacy of conventional therapeutics in PCa cells and (2) the efficacy of novel therapeutics in preclinical models of PCa to assess the translational potential of ceramide-based therapeutics for PCa. The novelty of the proposed work will result in delineating novel lipid-centric molecular mechanisms in prostate cancer that can impact novel therapeutics for patients with no current viable options. In the K00 component of this proposal, the impact of epigenetic marks in the regulation of lipid metabolism in tumors will be determined. I will also determine how manipulating lipid metabolism impacts the epigenome in cancer cells. Moreover, understanding the regulation between epigenetics and lipid biology in tumors will allow for target identification and recognition of the key pathways regulating these crucial machineries in cancer.

项目摘要/摘要前列腺癌（PCA）是全球和目的地大量男性中第二大事件的癌症研究，对这种疾病的治疗仍然难以捉摸。前列腺受男性恐怖调节（例如激活雄激素受体（AR）以触发器官中涉及信号通路的睾丸激素）发展与成长。在PCA中，这些骑兵在发作和进展中发挥重要作用疾病，因此已成为PCA患者的主要治疗靶点。但是，几乎所有患者复发和发展耐castration-PCA（CRPC），该疾病的致命阶段。因此新颖和对于PCA患者，更有效的治疗极为重要。在该项目的F99阶段中，将检查基于鞘脂的PCA治疗的潜力。神经酰胺纳米脂质体（CNL）在导致侵略性体外模型的细胞死亡方面非常有效 PCA和这些脂质体与FDA批准的药物结合使用时也具有治疗潜力 AR信号轴。工作假设是AR调节鞘脂代谢，以阻碍效率 PCA中的CNL。为了研究雄激素受体和神经酰胺代谢之间的关系，我们将特别研究（1）AR调节神经酰胺代谢的机制以及这如何影响常规疗法在PCA细胞中的功效和（2）临床前模型中新型治疗剂的效率 PCA评估基于神经酰胺的PCA治疗的翻译潜力。提议的新颖性工作将导致描述前列腺癌中新型以脂质为中心的分子机制，以影响新颖针对当前没有可行选择的患者的治疗方法。在该提案的K00组成部分中，表观遗传标记在调节脂质代谢中的影响在肿瘤中将确定。我还将确定操纵脂质代谢如何影响表观基因组癌细胞。此外，了解肿瘤中表观遗传学和脂质生物学之间的调节将允许为了确定和识别癌症中这些关键机器的关键途径。