The involvement of LIM kinase in metastases

描述（由申请人提供）：大多数癌症死亡是由于我们无法预防和/或治疗转移性疾病。一旦肿瘤发生转移，它们通常对可能对原发肿瘤有效的治疗具有抗性。迫切需要确定调节转移的分子事件，以便开发有效的治疗方法。该项目旨在确定激酶LIMK1在转移过程中的作用，LIMK1是肌动蛋白聚合的调节剂。细胞运动是转移过程中的重要步骤，我们已经证明LIMK1可以通过其促进肌动蛋白聚合的能力来调节运动和侵袭。在一些初步的实验中，我们还证明了在表达升高的LIMK1活性的细胞中增强的骨转移和通过表达显性阴性形式的LIMK1抑制这种转移。在一个合作项目中，我们汇集了三个领域的专业知识：克隆和定义LIMK1在细胞中作用的分子生物学家;具有明确定义和良好表征的转移模型的肿瘤生物学家，其中可以探索LIMK1的作用;以及一位在定义蛋白质三维结构方面有着良好记录的蛋白质化学家，他将解决LIMK1的结构，以期设计小分子抑制剂。我们的目标是测量LIMK1在人类癌症中的表达，包括乳腺癌和前列腺癌，这些癌症通常转移到骨骼。我们将从澳大利亚几家医院获得的大样本队列中将原发肿瘤和转移瘤（如果可用）中的LIMK1表达与临床结果相关联。然后，我们将扩展动物研究，在几个乳腺和前列腺转移模型中寻找LIMK1表达对转移能力的影响。这些模型包括乳腺癌从乳腺到骨的自发转移的独特模型。最后，我们将制备重组LIMK1用于产生晶体以解析其三级结构。这些实验将使我们能够确定LIMK1在转移中的作用，最终目标是将其用于转移性癌症的诊断和开发抑制这种激酶活性的化合物。

DESCRIPTION (provided by applicant): 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.