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    Research Grants Awarded

    Molecular Therapeutics of Breast-Associated Cancer Lymphedema

    Study Section:
    Treatment

    Scientific Abstract:
    Background Lymphedema, a common but often under-recognized disease, affects millions of breast cancer survivors in this country and throughout the world. In the past, little has been known about the biology of the cutaneous tissue responses to lymph stagnation. To investigate the tissue responses to lymphatic vascular insufficiency, we have developed and studied a murine model of acquired lymphatic insufficiency that closely simulates human breast cancer lymphedema. In the model, we have identified the characteristic histopathology and have identified specific genes and processes which are activated during disease progression. Objective/Hypothesis: The objective is to use this disease model to test several pharmacologic strategies for treatment of acquired lymphedema which are targeted at these specific molecular pathways. We hypothesize that the agents selected will have the pharmacological ability to minimize or reverse the pathological tissue responses to lymph stagnation. Specific Aims: (1) to test the hypothesis that specific inflammatory pathways are important in the genesis of lymphedema through pathway-specific blockade; and (2) to assess the utility of a mouse model of cutaneous lymphedema for the evaluation of responsiveness of this disease to therapeutic interventions. Study Design: We will investigate 6 distinct pharmacologic classes: a soluble TNF?Ñ receptor; a phosphodiesterase type 4 (PDE4) inhibitor of TNF?Ñ production; a 5-lipoxygenase activating protein (FLAP) inhibitor; a PPAR?× agonist; a Rho-kinase inhibitor; and a salicylate (aspirin). For each drug, we will surgically induce lymphedema in the murine tail and compare responses to normal and sham-surgical controls. Function will be assessed through serial tail volume quantitation. Cutaneous histopathology will be correlated with the molecular responses via microarray and rtPCR analyses, which will also be used to assess specific molecular responses within the inhibited pathways. Impact: This proposal will address a previously unmet need. Millions of breast cancer survivors have lymphedema, a disease that causes chronic swelling, pain, and loss of mobility following damage to the lymphatic circulation. Current treatment options are very limited and not highly successful. We propose to address the problem of acquired lymphedema through the rational development of drug therapy; if successful, these studies will provide an avenue to help the millions of breast cancer survivors whose quality of life is impaired by lymphedema. Given the strong parallels between the experimental model and histological responses in human lymphedema, coupled with the proven ability of these drug classes to favorably impact the molecular pathways identified in the preliminary studies of the model, there is a high likelihood that this proposal will identify a clinically relevant, therapeutically effective pharmacological approach to the amelioration of human breast cancer-associated lymphede

    Lay Abstract:
    Lymphedema is a common complication of successful breast cancer treatment by surgery and radiation therapy. The unavoidable damage to the lymphatic system leads to chronic swelling and disability in the arm on the previously affected side. This condition, often leading to loss of function and chronic pain, has a direct and distinct impact on quality-of-life in breast cancer survivors. Often under-recognized, lymphedema affects millions of breast cancer survivors in this country and throughout the world. Few, if any, effective treatments are available. In the past, little has been known about the biology of the condition. What is critical is to understand how the tissues respond to the presence of impaired lymph flow. In an attempt to generate answers to these questions, we have previously developed and studied a model of breast cancer lymphedema in the mouse tail. This model closely simulates the behavior of the human disease. Using this model, we have identified performed microscopic and molecular analysis of the tissues, in order to identify the biological ¡¥fingerprint¡¦ of the tissue responses in lymphedema. We have learned that inflammation plays an extraordinary role in the condition. Prompted by this initial information, we have also demonstrated that at least one form of systemic treatment with an anti-inflammatory drug can substantially restore normal tissue architecture and molecular signal. Our goal in this study is to use our animal model as an investigative platform to undertake rational identification of effective drug treatment to improve or reverse the tissue pathology of breast cancer lymphedema. We have identified six drug classes that have the capacity to favorably impact the molecular pathways that are abnormally activated in the experimental disease. We will test a member of each of these classes in our experimental model, to identify the one with the greatest capacity to normalize the disease manifestations. We propose to address the problem of acquired lymphedema through the rational development of drug therapy; if successful, these studies will provide an avenue to help the millions of breast cancer survivors whose quality of life is impaired by lymphedema. Given the strong parallels between the experimental model and histological responses in human lymphedema, coupled with the proven ability of these drug classes to favorably impact the molecular pathways identified in the preliminary studies of the model, there is a high likelihood that this proposal will identify a clinically relevant, therapeutically effective pharmacological approach to the amelioration of human breast cancer-associated lymphedema.