Macrophage COX-2 as a target in breast cancer chemoprevention

描述(申请人提供)：尽管在预防和治疗方面取得了进展，乳腺癌仍然是女性癌症相关死亡的第二大原因。随着该领域寻找新的方法，特别是对于雌激素受体阴性的疾病，调节慢性肿瘤炎症和逆转免疫抑制的策略显示出重大的前景。这样的治疗需要在肿瘤微环境中识别有效的分子靶点。环氧合酶-2(COX-2)是临床上公认的预防癌症的有效靶点。然而，已证实的全身性COX-2抑制的抗肿瘤益处是由于肿瘤中COX-2-前列腺素E_2的减少，伴随着不必要的内皮COX-2-前列环素的丢失，增加了血栓形成的风险。我们询问，系统性COX-2抑制的抗肿瘤和促血栓形成作用之间的机制差异是否为非系统性COX-2抑制提供了新的分子靶点，从而在不增加血栓形成的情况下抑制肿瘤。在最近的研究中，最初在本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)足以通过抑制浸润性细胞毒性T淋巴细胞而有力地减少乳腺肿瘤的发生(Chen等人，2013年再次提交给癌症研究)。现在，在R03的重新提交中，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，而不会增加血栓形成的风险。高密度脂蛋白(高密度脂蛋白)是一种可生物降解和生物相容的纳米颗粒，天然以巨噬细胞为靶点。在具体目标1中，我们将使用重组的(R)高密度脂蛋白纳米颗粒选择性地将COX-2抑制剂输送到巨噬细胞。我们将建立选择性抑制巨噬细胞COX-2的持续抗血栓内皮细胞COX-2活性。在特定的目标2中，我们将在两个HER2/neu诱导的疾病模型中，建立纳米治疗的有效性，与系统抑制COX-2相比，延迟乳腺癌的发病，减轻疾病负担，减缓肿瘤生长和改善肿瘤微环境。在R03中取得成功的可能性很大--靶细胞巨噬细胞COX-2在乳腺肿瘤模型中得到验证，rHDL巨噬细胞靶向方法被建立，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大学医学院纳米医学计划之间新的跨学科合作的开始，该计划为未来rHDLCOX-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，以抑制乳腺癌和其他癌症。我们的首要目标是一种安全有效的方法，以实现COX-2抑制在癌症预防和治疗中的前景，而不会对心血管造成危害。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影响，特别是在高危个人和家庭中。

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.