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Targeting the Opioidergic and Adrenergic Systems to Control Breast Cancers

针对阿片能和肾上腺素能系统来控制乳腺癌

基本信息

批准号：
10153710
负责人：
DIPAK KUMAR SARKAR
金额：
$ 31万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153710
关键词：
ADRB2 gene Abbreviations Address Adrenal Glands Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Affect Agonist American Animal Model Animals Anti-Inflammatory Agents Apoptosis Biochemical Markers Blood Circulation Brain Breast Cancer Cell Breast Cancer Risk Factor Breast Cancer cell line Cancer Cell Growth Carcinogens Cell Therapy Cell Transplantation Cell physiology Cells Chronic Clinic Combined Modality Therapy Cyclic AMP-Dependent Protein Kinases Development Dimerization Disease Disease Outcome Dose ERBB2 gene Effectiveness Endorphins Enkephalin, D-Penicillamine (2,5)-Enkephalins Epithelial Equilibrium Ethnic group G-Protein-Coupled Receptors Genes Goals Growth Human Hypothalamic structure Immune Immune response Immune system Immunologic Surveillance In Vitro Incidence Inflammation Inflammatory Interferon Type II Interferons Interleukin-6 Intervention Label Ligand Binding Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Measures Mesenchymal Molecular Mus Natural Increases Natural Killer Cells Nature Neoplasm Metastasis Neurons Nude Rats Opioid Opioid Receptor Opioid agonist PTEN gene Patients Penicillamine Peripheral Blood Mononuclear Cell Pharmacology Physiology Pituitary Gland Prevalence Prevention Pro-Opiomelanocortin Procedures Prognosis Prognostic Factor Race Rattus Receptor Down-Regulation Regulation Research Project Grants Signaling Molecule Site Small Interfering RNA Spleen Stress Subgroup System TNF gene Techniques Testing Transplantation Treatment outcome Tumor Burden Tumor Subtype Tumor Tissue Tumor-Derived Variant Vascular Endothelial Growth Factors Western Blotting Woman Xenograft Model Xenograft procedure alpha-Melanocyte stimulating hormone anticancer research beta-2 Adrenergic Receptors beta-Endorphin black women cancer prevention cell growth chemokine cytokine cytotoxic delta opioid receptor design dimer drug action effective therapy epithelial to mesenchymal transition experimental study gene repression humanized mouse immune function improved in vivo knock-down macrophage malignant breast neoplasm molecular subtypes mu opioid receptors neoplastic cell novel opioid agonist therapy paraventricular nucleus prevent protective effect racial and ethnic receptor receptor binding receptor function response subcutaneous targeted agent treatment strategy tumor tumor growth tumor microenvironment tumor xenograft tumor-immune system interactions

项目摘要

Breast tumors vary in their molecular subtypes (luminal A, Luminal B, triple negative/basal-like and Her2 type). Disparities in breast cancer persist in all types. The prevalence rates and prognosis of the four subtypes of breast cancer appear to differ by race in the US. Recent studies have identified the immune response in the tumor microenvironment of both HER2+ and basal tumors an important prognostic factor. We have recently shown that intervention related to reduction of body stress via endorphin cell therapy into the brain suppresses carcinogen-induced mammary tumor incidence, growth, malignancy rate, and metastasis in rat animal models by increasing immune activities and altering inflammatory conditions in the tumor microenvironment. The beneficial effect of endorphin cell therapy on cancer growth involves activation of the opioidergic system and suppression of the adrenergic system in rats. We hypothesize that pharmacological agents targeting both the opioidergic system and beta2-adrenergic system might offer an effective therapy for growth prevention of all types of breast cancer cells. Furthermore, we hypothesize that simultaneous activation of delta-opioid receptors and suppression of beta2-adrenergic receptors will be most effective. To test these hypotheses we will employ established breast cancer cell lines and primary human tumor tissues that represent various breast tumor subtypes in xenografts in athymic nude rats and humanized NSG mice. We will determine the efficacy of a combined treatment of a delta-opioid receptor agonist and a beta2-adrenergic receptor antagonist in reducing the growth and invasiveness in xenografts. We will determine effects of these agents on tumor cell physiology by measuring various biochemical markers and signaling molecules of proliferation, apoptosis and epithelial mesenchymal transition. We will study whether opioidergic and adrenergic agents alter immune cell functions to affect tumor cell physiology. Furthermore, we will evaluate if the cross talk between opioidergic and adrenergic agents is due to receptor dimerization on immune cells and/or breast tumor cells. We will employ various cellular and molecular approaches, receptorology and gene knockdown techniques to investigate molecular actions of opioidergic and beta2-adrenergic agents on breast cancer cell growth and progression. Together these studies should show the effectiveness of combining an opioid agonist and beta2-adrenergic antagonist for preventing growth of various types of breast cancer cells that may be easily translatable to clinic for the treatment of patients with various subtypes of breast cancers.

乳腺肿瘤的分子亚型各不相同（Luminal A、Luminal B、三阴性/基底样和 Her2 型）。所有类型的乳腺癌都存在差异。四种亚型的患病率及预后在美国，乳腺癌似乎因种族而异。最近的研究已经确定了免疫反应 HER2+和基底肿瘤的肿瘤微环境是重要的预后因素。我们最近有研究表明，通过大脑内啡肽细胞疗法减少身体压力相关的干预措施会抑制大鼠动物模型中致癌物诱发的乳腺肿瘤的发生率、生长、恶性率和转移通过增加免疫活性和改变肿瘤微环境中的炎症条件。这内啡肽细胞疗法对癌症生长的有益作用涉及阿片能系统的激活和抑制大鼠肾上腺素能系统。我们假设针对这两种药物的药物阿片类药物系统和β2-肾上腺素能系统可能为所有儿童的生长预防提供有效的治疗方法乳腺癌细胞的类型。此外，我们假设同时激活 δ-阿片类药物受体和抑制β2-肾上腺素能受体将是最有效的。为了检验这些假设，我们将采用已建立的乳腺癌细胞系和代表各种乳腺癌的原发性人类肿瘤组织无胸腺裸鼠和人源化 NSG 小鼠异种移植物中的肿瘤亚型。我们将确定疗效 δ-阿片受体激动剂和β2-肾上腺素能受体拮抗剂联合治疗的研究减少异种移植物的生长和侵袭。我们将确定这些药物对肿瘤细胞的影响通过测量各种生化标志物和增殖、凋亡和信号分子的生理学上皮间质转化。我们将研究阿片类药物和肾上腺素类药物是否会改变免疫细胞功能影响肿瘤细胞的生理学。此外，我们将评估阿片类药物之间是否存在串扰肾上腺素能药物是由于免疫细胞和/或乳腺肿瘤细胞上的受体二聚化所致。我们将采用各种细胞和分子方法、受体学和基因敲除技术研究阿片类药物和 β2 肾上腺素类药物对乳腺癌细胞生长的分子作用进展。这些研究共同表明阿片类激动剂和 β2 肾上腺素能药物联合使用的有效性用于预防各种类型乳腺癌细胞生长的拮抗剂，可轻松转化为临床用于治疗患有各种亚型乳腺癌的患者。