Macrophage COX-2 as a target in breast cancer chemoprevention

巨噬细胞 COX-2 作为乳腺癌化学预防的靶点

基本信息

批准号：
8842600
负责人：
David Peter Cormode
金额：
$ 8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8842600
关键词：
Address Adverse effects Affinity Anti-Inflammatory Agents Anti-inflammatory Aspirin Biocompatible Biological Biology Breast Breast Cancer Model Breast Cancer Treatment Cancer Center Cancer Etiology Cardiovascular system Cessation of life Chronic Clinical Clinical Research Clinical effectiveness Collaborations Complex Coxibs Cytotoxic T-Lymphocytes Data Development Dinoprostone Disease ERBB2 gene Endothelium Environment Enzymes Epoprostenol Estrogen receptor negative Event Family Foundations Future Goals Health High Density Lipoproteins Ibuprofen Immune Immunosuppression Individual Inflammation Inflammatory Institutes Link Lymphocyte Function Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Medicine Modeling Molecular Target Mus Pharmaceutical Preparations Prevention Prostaglandins I Public Health Publishing Reagent Research Risk Risk Reduction Source System Therapeutic Therapeutic Studies Thrombosis Translating Translations Tumor Suppression Woman Work anticancer research base burden of illness cancer chemoprevention cancer prevention cancer risk cancer therapy celecoxib cyclooxygenase 2 gastrointestinal hazard head-to-head comparison high risk in vivo innovation macrophage malignant breast neoplasm medical schools mouse model nanomedicine nanoparticle nanotherapeutic nanotherapy neoplastic cell novel novel strategies pre-clinical programs reconstitution safety study success tumor tumor growth tumor microenvironment tumor progression unpublished works

项目摘要

DESCRIPTION (provided by applicant): Despite progress in prevention and treatment, breast cancer remains the second leading cause of cancer- related death in women. As the field seeks new approaches, especially for estrogen receptor-negative disease, strategies to modulate chronic tumor inflammation and reverse immune suppression show significant promise. Such therapies require identification of effective molecular targets in the tumor microenvironment. Cyclooxygenase-2 (COX-2) is an established and clinically effective target in cancer prevention. However, the proven anti-tumor benefit of systemic COX-2 inhibition, which results from reduced of COX-2-prostaglandin E2 in tumors, is accompanied by unwanted loss of endothelial COX-2-prostacyclin, elevating thrombotic risk. We asked if the established mechanistic distinctions between the anti-tumor and pro-thrombotic effects of systemic COX-2 inhibition provide novel molecular targets for non-systemic COX-2 inhibition to suppress tumors without increasing thrombosis. In recent studies, proposed originally in the 1st submission of this R03, we determined that selective deletion of macrophage cyclooxygenase-2 (COX-2) was sufficient to robustly reduce mammary tumorigenesis by suppressing infiltrating cytotoxic T-lymphocytes (Chen et al., 2013 resubmitted to Cancer Research). Now, in this R03 resubmission, we propose to translate these exciting new findings to an innovative nanotherapeutic approach to suppress mammary tumors without elevating thrombotic risk by selective inhibition of macrophage COX-2. High-density lipoprotein (HDL) is a biodegradable and biocompatible nanoparticle that naturally targets macrophages. In Specific Aim 1 we will use reconstituted (r) HDL nanoparticles to selectively deliver a COX-2 inhibitor to macrophages. We will establish selective inhibition of macrophage COX-2 with sustained anti- thrombotic endothelial COX-2 activity. In Specific Aim 2 we will establish the efficacy of the nanotherapy, compared to systemic COX-2 inhibition, to delay mammary tumor onset, reduce disease burden, slow tumor growth and modify the tumor microenvironment, in two models of her2/neu-induced disease. Success in this R03 is highly likely - the target, macrophage COX-2, is validated in mammary tumor models, the approach, rHDL macrophage targeting, is established, and we have the necessary models, reagents and expertise. This resubmission is the beginning of a new cross-disciplinary collaboration between UPenn's Institute for Translation Medicine and Therapeutics and Mt Sinai School of Medicine's Nanomedicine Program that lays the foundation for future pre-clinical and clinical therapeutic and safety studies of rHDL COX-2 inhibitor nanotherapy to suppress breast and other cancers. Our overarching goal is a safe and effective approach to realize the promise of COX-2 inhibition in cancer prevention and treatment without cardiovascular hazard. Development of such a targeted nanotherapeutic may have a profound impact on public health and cancer prevention and therapy especially in high-risk individuals and families.

描述（由申请人提供）：尽管预防和治疗方面取得了进展，但乳腺癌仍然是女性癌症相关死亡的第二大原因。当该领域寻求新方法，尤其是对于雌激素受体阴性疾病时，调节慢性肿瘤炎症和反向免疫抑制的策略显示出很大的希望。这种疗法需要鉴定肿瘤微环境中的有效分子靶标。环氧酶-2（COX-2）是癌症预防的确定且具有临床有效的靶标。然而，全身性COX-2抑制的经过验证的抗肿瘤益处是由肿瘤中COX-2-蛋白质E2降低的降低而导致的，伴随着内皮内皮COX-2-螺旋细胞的不必要丧失，升高了血栓形成风险。我们询问全身性COX-2抑制的抗肿瘤和促栓性作用之间建立的机械区别是否为非系统性COX-2抑制作用提供了新的分子靶标，可以抑制肿瘤而不增加血栓形成。在最初提出的最初是在此R03的第一项提议的最新研究中，我们确定巨噬细胞环氧合酶2（COX-2）的选择性缺失足以通过抑制细胞毒性的T-淋巴细胞来抑制浸润性T-乳细胞（Chen等人，2013年的癌症研究）。现在，在此R03重新提交中，我们建议将这些令人兴奋的新发现转化为一种创新的纳米疗法方法，以抑制乳腺肿瘤，而不会通过选择性抑制巨噬细胞COX-2来抑制血栓形成风险。高密度脂蛋白（HDL）是一种自然靶向巨噬细胞的可生物降解且具有生物相容性的纳米颗粒。在特定目标1中，我们将使用重构的（R）HDL纳米颗粒来选择性地将COX-2抑制剂传递到巨噬细胞。我们将建立对巨噬细胞COX-2的选择性抑制，并具有持续的抗血栓性内皮COX-2活性。在特定的目标2中，我们将建立纳米疗法的功效，与全身性COX-2抑制作用相比，延迟乳腺肿瘤发作，减轻疾病负担，缓慢的肿瘤生长并改变肿瘤微环境，在HER2/NEU诱导的两种模型中。在此R03中的成功很有可能 - 在乳腺肿瘤模型中验证了巨噬细胞COX -2，该方法是建立方法，即RHDL巨噬细胞靶向，并且我们具有必要的模型，试剂和专业知识。这种重新提交是UPENN翻译医学研究所与治疗学研究所与MT Sinai医学院纳米医学计划之间进行新的跨学科合作的开始，该计划为未来的临床前和临床治疗和安全性研究奠定了基础。我们的总体目标是一种安全有效的方法，可以实现COX-2在没有心血管危害的情况下抑制COX-2的希望。这种有针对性的纳米疗法的发展可能会对公共卫生和预防癌症和治疗产生深远的影响，尤其是在高危个人和家庭中。