The anti-tumorigenic and anti-metastatic potential of Eya phosphatase inhibitors

描述(申请人提供)：2012年，乳腺癌预计将导致39,510名美国女性死亡，全球将导致450,000人死亡。乳腺癌一旦扩散，基本上是无法治愈的。治疗晚期乳腺癌的一个关键障碍是缺乏对大部分癌症患者有效且毒性低的癌症特效药。Sixone Solutions，LLC建议评估一种开发广泛有效、低毒乳腺癌药物的新方法的可行性。以前的工作证实，由蛋白质Eya和SIX1组成的转录复合体在导致细胞癌变和扩散方面发挥着重要作用。这些蛋白质在早期胚胎发育中很重要，在正常的成年细胞中基本上是不存在的。然而，在某些癌症中，包括乳腺癌，它们会再次出现。许多乳腺癌已被证明含有高水平的这些蛋白质。降低EYA和SIX1水平的基因操作会使培养的癌细胞表现得更像正常细胞，并显著抑制小鼠模型中的肿瘤生长和扩散。第一阶段项目的设计是为了确定是否可以在药理学上达到同样的效果。Eya蛋白具有磷酸酶活性，这对Eya/SIX1复合体的致癌潜力是必不可少的。这种磷酸酶的活性部位不同于大多数其他细胞磷酸酶，这提供了一个独特的靶点。我们附属大学的研究人员已经发现了一类新的小分子，它们可以抑制Eya磷酸酶，但不能抑制其他细胞磷酸酶。拟议的第一阶段项目将确定这些化合物是否能够阻断EYA/SIX1的增殖、存活和转移活性。细胞培养分析将评估这些化合物对非癌乳腺上皮细胞系以及Eya和SIX1水平中等到高水平的乳腺癌细胞的影响。体内试验将评估注射了乳腺癌细胞并用化合物治疗的小鼠的转移和化疗敏感性。如果第一阶段项目成功，它将确立通过一种新的方法开发治疗乳腺癌的药物的可行性，可能还包括其他癌症。由于靶蛋白在很大比例的乳腺癌中过度表达，并且由于它们在正常组织中不表达或表达最低，这种方法可能在大量乳腺癌患者中广泛有效，且毒性低，满足了目前治疗晚期乳腺癌的需要。此外，小分子抑制剂的制造成本应该比目前以抗体为基础的乳腺癌治疗药物更便宜。

DESCRIPTION (provided by applicant): Breast cancer is expected to cause 39,510 deaths of American women in 2012 and 450,000 deaths globally. Once breast cancer has spread, it is essentially incurable. A critical barrier to treating advanced breast cancer is the lack of cancer-specific drugs that are effective in a large percentage of cancer patients and have low toxicity. Sixone Solutions, LLC proposes to evaluate the feasibility of a novel approach to developing widely effective, low toxicity breast cancer drugs. Previous work established that a transcriptional complex, consisting of proteins Eya and Six1, plays a significant role in causing cells to become cancerous and spread. These proteins are important in early embryo development and are essentially absent in normal adult cells. However, in certain cancers, including breast cancer, they reemerge. Many breast cancers have been shown to have high levels of these proteins. Genetic manipulation to reduce Eya and Six1 levels causes cultured cancer cells to act more like normal cells and significantly inhibit tumor growth and spread in mouse models. The Phase I project is designed to determine if the same effect can be achieved pharmacologically. The Eya protein has phosphatase activity that is essential to the cancer-causing potential of the Eya/Six1 complex. The active site of this phosphatase is different from most other cellular phosphatases, which offers a unique target. Our affiliated university investigators have identified a class of novel small molecules that inhibit the Eya phosphatase but not other cellular phosphatases. The proposed Phase I project will determine if these compounds can block the proliferation, survival, and metastatic activities of Eya/Six1. Cell culture assays will assess the impact of the compounds on non-cancerous mammary epithelial cell lines and mammary carcinoma cells with medium to high levels of Eya and Six1. In vivo assays will assess metastasis and chemosensitization in mice injected with breast cancer cells and treated with compound. If the Phase I project is successful, it will establish the feasibility f developing drugs to treat breast cancer, and possibly other cancers, through a new approach. Because the target proteins are overexpressed in a large percentage of breast cancers and because they are absent or minimally expressed in normal tissues, this approach could be broadly effective in a large number of breast cancer patients and have low toxicity, addressing the current needs in treating advanced breast cancer. In addition, small molecule inhibitors should be less expensive to manufacture that the current antibody-based breast cancer therapeutic.