The majority of cancer deaths are due to our inability to prevent and/or treat metastatic disease. Once tumors have metastasized, they are often resistant to the therapies that may have been effective on the primary tumor. There is an urgent need to define the molecular events that regulate metastasis so that effective therapies can be developed. This projects aims to define the role of a kinase, LIMK1, a regulator of actin polymerization, in the metastatic process. Cell motility is an essential step in the metastatic process and we have already shown that LIMK1 can regulate motility and invasion through its ability to promote actin polymerization. In some preliminary experiments, we have also demonstrated enhanced metastasis to bone in cells expressing elevated LIMK1 activity and inhibition of this metastasis by expression of a dominant negative form of LIMK1. In a collaborative program, we bring together three areas of expertise: a molecular biologist who cloned and defined the role of LIMK1 in cells; a tumor biologist with well defined and well characterized metastasis models in which the role of LIMK1 can be explored; and a protein chemist with a proven track record in defining the three dimensional structure of proteins, who will solve the structure of LIMK1 with a view to designing small molecule inhibitors.
Our aims are to measure LIMK1 expression in human cancers, including breast and prostate, which commonly metastasize to bone. We will correlate LIMK1 expression in primary tumors and in metastases (where available) with clinical outcome in large cohorts of samples accessed from several hospitals in Australia. We will then extend the animal studies, looking in several breast and prostate metastasis models for the influence of LIMK1 expression on metastatic capacity. These models include a unique model of spontaneous metastasis of breast cancer from the mammary gland to bone. Finally, we will prepare recombinant LIMK1 for generation of crystals to solve its tertiary structure. These experiments will allow us to establish the role of LIMK1 in metastases with the ultimate goal of using it for diagnosis of metastatic cancer and for developing compounds that inhibit the activity of this kinase.
| Li, Rong; Doherty, Judy; Antonipillai, Juliana et al. (2013) LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice. Clin Exp Metastasis 30:483-95 |
