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Novel Targeting of TGFb in Osteolytic Metastasis
Metastasis, the spread and growth of tumour cells to distant organs, represents the most devastating attribute of cancer. Bone metastasis is a particularly frequent site of metastasis in patients with carcinoma of the breast, and can cause severe morbidity in patients, including pain, pathological fractures, hypercalcemia and spinal cord compression leading to nerve damage and paralysis. Breast-to-bone metastasis therefore represents a distinct and significant clinical problem. Bisphosphonates, a class of drugs that inhibit the breakdown of bone, are proving useful in the management of bone pain from breast cancer, however approximately 50% of breast-to-bone metastases do not respond to bisphosphonate therapies, and there is very little impact on overall survival. This emphasizes the great need for additional therapies for breast-to-bone metastasis.
In a series of preliminary experiments, we have made the novel finding that the drug Tranilast produces marked suppression in incidence and onset of osteolytic lesions in two standard in vivo systems that model breast-to-bone metastasis. Tranilast is a non-toxic TGF-â antagonist that appears to exert its effect through suppression of TGF-â signalling and/or release and maturation of TGF-â from bound stores. Remarkably, there is little literature on experimental use of Tranilast in cancer systems and to our knowledge this drug has not been previously considered for use as an anti-osteolytic agent. This is despite the well established role of TGF-â in driving tumour-induced osteolysis. This application is to further evaluate the anti-osteolytic activity of Tranilast and define the molecular basis of action in the cancer/bone environment. There are two aims. Aim 1: Further evaluate the anti-osteolytic potential of Tranilast using in vivo models of metastasis. (a) Assess drug in two additional in vivo models of bone metastasis with associated osteolysis, (b) Examine dose escalation, dose-response and directly compare with bisphosphonates. Aim 2: Characterize and identify the cellular and molecular basis of anti-osteolytic action. (a) Determine if Tranilast impacts on TGF-â signalling pathways, (b) Determine if Tranilast suppresses TGF-â release and activation from bone extracellular matrix, (c) Cellular and molecular characterization of Tranilast-responding osteolytic tumors: Immunohistochemistry and microarray expression profiling studies. Should the activity of this drug continue to deliver encouraging results, our additional goal during the final year of the grant will be to initiate planing for a clinical trial.
The spread of cancer from its original site to distant sites is a complex, multi-step process that is a major cause of death and morbidity amongst cancer patients. In breast cancer, metastasis to bone occurs frequently and causes significant problems including pain, fracture, immobility, and paralysis. Bisphosphonates, a class of drugs that inhibit the breakdown of bone, are proving useful in the management of bone pain in cancer patients with bone metastasis, however approximately 50% of breast-to-bone metastases do not respond to bisphosphonate therapies. There is therefore a great need for additional therapies.
We have recently found that Tranilast, a TGFâ antagonist widely used in Japan for skin disorders, reduces the incidence and severity of breast-to-bone metastasis in two well-accepted animal models of the disease. Remarkably, there is little literature on experimental use of Tranilast in cancer systems despite heavy implication of TGFâ, and to our knowledge this drug has not been previously considered for use as an anti-osteolytic agent. As Tranilast is a safe and registered drug for non-cancer related disorders, it therefore has the potential to rapidly become a treatment option for breast cancer patients suffering, or at risk of developing, bone metastasis. We do however need a better understanding the molecular basis for anti-osteolytic action for this drug to better direct subsequent clinical trial in human patients.
We aim to further explore and exploit the anti-osteolytic potential of Tranilast by: (1) Examining dose escalation, dose-response and directly comparing with the leading bisphosphonate drug in our established mouse models of breast-to-bone metastasis, (2) Assessing drug in two additional animal models of bone metastasis with associated osteolysis, (3) Determining if Tranilast impacts on cancer cell communication pathways; in particular TGFâ communication pathways, (4) Determining if Tranilast suppresses TGFâ release and activation from bone extracellular matrix, (5) Performing specialized cellular and molecular characterization studies of Tranilast-responding osteolytic tumors. Should the activity of this drug continue to deliver encouraging results, our additional goal during the final year of the grant will be to initiate planing for a clinical trial. If executed successfully, this study may pave the way for the introduction of Tranilast as a new agent to treat the significant clinical problem of cancer-induced osteolysis.