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Developing Novel Therapies for Treating Breast-Cancer-Related Lymphedema

开发治疗乳腺癌相关淋巴水肿的新疗法

基本信息

批准号：
8647758
负责人：
SHEAU-YU Teddy HSU
金额：
$ 22.5万
依托单位：
ADEPTHERA, LLC
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：
2014-09-18 至 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647758
关键词：
Adipose tissue Adult Affect Angiopoietins Animal Model Apoptosis Attention Axillary Lymph Node Dissection Blood Blood Vessels Breast Cancer Patient Cancer Survivor Cell Therapy Cells Chronic Chronic Disease Combined Modality Therapy Development Dose Edema Effectiveness Embryonic Development Excision Exercise Exhibits Extravasation Fibrosis Functional disorder Growth Factor Health Care Costs Healthcare Systems Hormones Human In Vitro Individual Infection Inflammation Injury Lead Ligands Limb structure Liquid substance Lymph Lymphangiogenesis Lymphatic Lymphatic System Lymphatic vessel Lymphedema Maintenance Massage Medical Modeling Mus Natural regeneration Operative Surgical Procedures Pain Patients Pelvic Cancer Peptides Permeability Physical therapy Play Predisposition Principal Investigator Property Proteins RAMP1 Radiation therapy Regulation Risk Rodent Role Skin Care Stem cells Swelling Tachycardia Therapeutic Tissues Transplantation Vascular Endothelial Growth Factors Vascular Permeabilities absorption adrenomedullin analog base breast cancer diagnosis cancer surgery chemotherapy compliance behavior drug candidate effective therapy improved in vivo lymph nodes malignant breast neoplasm novel novel strategies novel therapeutics peptide analog prevent primary lymphedema programs psychologic public health relevance receptor reconstitution regenerative stem stem cell therapy

项目摘要

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.

描述（由申请方提供）：在通过手术和/或放射治疗治疗乳腺癌的过程中，淋巴管的破坏可导致继发性水肿的发生。乳腺癌相关性水肿与肢体肿胀、慢性炎症、组织纤维化和感染易感性增加有关。据估计，美国230万乳腺癌幸存者中约有20%在腋窝淋巴结清扫和放射治疗后患有这种慢性疾病。目前对继发性水肿的治疗仅限于终身物理治疗，这可能对大多数患者造成大量甚至令人望而却步的经济、身体和心理压力。显然，有一个未满足的，但迫切的医疗需要的新方法来治疗乳腺癌幸存者的水肿。有趣的是，最近的发现表明，两个人类的肿瘤-肾上腺髓质素（ADM）和intermedin（IMD/ADM 2）-和它们的同源受体（ADM/RAMP 1，2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，脂肪组织来源的祖细胞（ADRCs）可以促进淋巴管形成在水肿模型。由于乳腺癌幸存者可能被剥夺了对淋巴管再生至关重要的内皮祖细胞，我们假设整合了β-内酰胺酶/RAMP受体配体和ADRCs的联合治疗可能是预防水肿发生或减少水肿衰弱效应的最有效方法。为了充分发挥在这种联合治疗中，已经开发出一组在体内表现出延长的生物活性的稳定的ADM和IMD类似物。因此，我们提出研究包括ADRC的联合疗法的效力，并选择稳定的类似物，以改善小鼠继发性水肿模型中淋巴管的再生。这种新型联合疗法的成功开发有可能减少乳腺癌幸存者中乳腺癌相关性水肿的衰弱效应。