Developing Novel Therapies for Treating Breast-Cancer-Related Lymphedema

描述(申请人提供)：在通过手术和/或放射治疗治疗乳腺癌的过程中，淋巴管的破坏可能会导致继发性淋巴水肿。与乳腺癌相关的淋巴水肿与衰弱的肢体肿胀、慢性炎症、组织纤维化和感染易感性增加有关。据估计，在美国230万乳腺癌幸存者中，约有20%的人在腋窝淋巴结清扫和放射治疗后患有这种慢性疾病。目前对继发性淋巴水肿的治疗仅限于终身理疗，这可能会给大多数患者带来巨大的、甚至是令人望而却步的经济、身体和心理压力。显然，治疗乳腺癌幸存者淋巴水肿的新方法尚未得到满足，但医学上仍有迫切的需求。有趣的是，最近的发现表明，两种人类激素-肾上腺髓质素(ADM)和间质(IMD/ADM2)-及其同源受体(CLR/RAMP1、2和3受体)在淋巴管生成和内皮通透性的调节中发挥关键作用，脂肪组织衍生的祖细胞(ADRC)可以促进淋巴管的形成。由于乳腺癌幸存者可能被剥夺了淋巴管再生所必需的内皮祖细胞，我们推测，整合CLR/RAMP受体配体和ADRC的联合治疗可能是预防淋巴水肿发生或减少淋巴水肿的最有效的方法。充分发挥……的潜力 这种联合疗法，已经开发出一组稳定的ADM和IMD类似物，在体内表现出长期的生物活性。因此，我们建议研究包含ADRC的联合疗法的有效性，并选择稳定的类似物来改善小鼠继发性淋巴水肿模型中淋巴管的再生。这种新的联合疗法的成功开发有可能减少乳腺癌幸存者中与乳腺癌相关的淋巴水肿的衰弱效应。

DESCRIPTION (provided by applicant): Destruction of lymphatic vessels during the treatment of breast cancer by surgery and/or radiation therapy can lead to the development of secondary lymphedema. The breast-cancer-related lymphedema is associated with debilitating limb swelling, chronic inflammation, tissue fibrosis, and increased susceptibility to infection. It has been estimated that approximately 20% of the 2.3 million breast cancer survivors in the US suffer this chronic condition following axillary lymph node dissection and radiation therapy. Current treatments for secondary lymphedema are limited to lifelong physiotherapies, which can cause substantial and even prohibitive financial, physical, and psychological strain for most patients. Clearly, there is an unmet yet urgent medical need for new approaches to treat lymphedema in breast cancer survivors. Interestingly, recent discoveries have shown that two human hormones-adrenomedullin (ADM) and intermedin (IMD/ADM2)-and their cognate receptors (CLR/RAMP1, 2, and 3 receptors) play critical roles in the regulation of lymphangiogenesis and endothelial permeability, and that adipose tissue-derived progenitor cells (ADRCs) can promote lymphatic vessel formation in lymphedema models. Because breast cancer survivors may be deprived of endothelial progenitor cells that are essential for the regeneration of lymphatic vessels, we hypothesize that a combination therapy that integrates a CLR/RAMP receptor ligand and ADRCs could be the most efficient approach to prevent the occurrence of or to reduce the debilitating effects of lymphedema. To realize the full potential of this combination therapy, a group of stable ADM and IMD analogs that exhibit prolonged bioactivity in vivo have been developed. Accordingly, we propose to investigate the potency of combination therapies that comprise ADRCs and select stable analogs in improving the regeneration of lymphatic vessels in a mouse secondary lymphedema model. Successful development of this novel combination therapy has the potential to decrease the debilitating effects of breast-cancer-related lymphedema among breast cancer survivors.