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：
10413258
负责人：
Pedro Filipe Da Costa Pinheiro
金额：
$ 7.78万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10413258
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 Hi-C 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 translational potential 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.

项目概要/摘要前列腺癌 (PCa) 是全世界男性中第二高发病率的癌症，尽管有大量研究表明，这种疾病的治疗仍然难以捉摸。前列腺受雄性激素（例如男性荷尔蒙）的调节。睾酮）激活雄激素受体（AR）以触发参与器官功能的信号通路在 PCa 的发育和生长中，这些激素在 PCa 的发生和进展中发挥着重要作用。疾病，因此一直是 PCa 患者的主要治疗靶点。复发并发展为去势抵抗性前列腺癌（CRPC），这是该疾病的致死阶段，因此是新颖且新颖的。更有效的治疗对于前列腺癌患者极为重要。在该项目的 F99 阶段，将检查基于鞘脂的前列腺癌疗法的潜力。神经酰胺纳米脂质体 (CNL) 在导致侵袭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 批准的靶向药物结合使用时也具有治疗潜力 AR 信号轴的工作假设是 AR 调节鞘脂代谢，从而阻碍功效。为了研究雄激素受体与神经酰胺代谢之间的关系，我们将具体研究（1）AR调节神经酰胺代谢的机制及其如何影响传统疗法在 PCa 细胞中的疗效以及 (2) 治疗新药在临床前模型中的功效 PCa 评估基于神经酰胺的 PCa 疗法的转化潜力。这项工作将导致描绘前列腺癌中新的以脂质为中心的分子机制，该机制可以影响新的为目前没有可行选择的患者提供治疗。在该提案的K00部分中，表观遗传标记在脂质代谢调节中的影响我还将确定操纵脂质代谢如何影响表观基因组。此外，了解肿瘤中表观遗传学和脂质生物学之间的调节将有助于实现。用于目标识别和识别调节癌症中这些关键机制的关键途径。