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pre-clinical programs reconstitution safety study success tumor tumor growth tumor microenvironment tumor progression unpublished works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）：尽管在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。随着该领域寻求新的方法，特别是针对雌激素受体阴性疾病，调节慢性肿瘤炎症和逆转免疫抑制的策略显示出巨大的前景。此类疗法需要识别肿瘤微环境中的有效分子靶点。环加氧酶-2 (COX-2) 是癌症预防的既定且临床有效的靶标。然而，全身性 COX-2 抑制（由于肿瘤中 COX-2-前列腺素 E2 减少）已被证实具有抗肿瘤功效，但同时也会导致内皮 COX-2-前列环素不必要的损失，从而增加血栓形成的风险。我们询问全身性 COX-2 抑制的抗肿瘤作用和促血栓形成作用之间已建立的机制差异是否为非全身性 COX-2 抑制提供新的分子靶标，以抑制肿瘤而不增加血栓形成。在最近的研究中，最初在该 R03 的第一次提交中提出，我们确定选择性删除巨噬细胞环氧合酶-2 (COX-2) 足以通过抑制浸润的细胞毒性 T 淋巴细胞来强有力地减少乳腺肿瘤发生（Chen 等，2013）重新提交给癌症研究）。现在，在这次 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治疗方法，通过选择性抑制巨噬细胞 COX-2 来抑制乳腺肿瘤，而不增加血栓形成风险。高密度脂蛋白（HDL）是一种可生物降解且具有生物相容性的纳米颗粒，天然靶向巨噬细胞。在具体目标 1 中，我们将使用重构的 (r) HDL 纳米颗粒选择性地将 COX-2 抑制剂递送至巨噬细胞。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内皮 COX-2 活性。在具体目标 2 中，我们将在两个 her2/neu 诱导疾病模型中确定纳米疗法与全身 COX-2 抑制相比的功效，以延迟乳腺肿瘤发病、减轻疾病负担、减缓肿瘤生长并改变肿瘤微环境。 R03 的成功可能性很大——目标巨噬细胞 COX-2 在乳腺肿瘤模型中得到验证，rHDL 巨噬细胞靶向方法已经建立，我们拥有必要的模型、试剂和专业知识。这次重新提交是宾夕法尼亚大学转化医学和治疗研究所与西奈山医学院纳米医学项目之间新的跨学科合作的开始，为未来 rHDL COX-2 抑制剂纳米疗法的临床前和临床治疗及安全性研究奠定了基础抑制乳腺癌和其他癌症。我们的首要目标是找到一种安全有效的方法来实现 COX-2 抑制在癌症预防和治疗中的承诺，且不会危害心血管。这种靶向纳米疗法的开发可能会对公共卫生和癌症预防和治疗产生深远的影响，特别是对高危个人和家庭。