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

描述（由申请人提供）：预计 2012 年乳腺癌将导致 39,510 名美国女性死亡，全球 450,000 名女性死亡。乳腺癌一旦扩散，基本上就无法治愈。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异性药物。 Sixone Solutions, LLC 提议评估一种开发广泛有效、低毒性乳腺癌药物的新方法的可行性。先前的研究表明，由蛋白质 Eya 和 Six1 组成的转录复合物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，并且在正常成体细胞中基本上不存在。然而，在某些癌症中，包括乳腺癌，它们会重新出现。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 水平的基因操作使培养的癌细胞表现得更像正常细胞，并显着抑制小鼠模型中的肿瘤生长和扩散。第一阶段项目旨在确定是否可以在药理学上实现相同的效果。 Eya 蛋白具有磷酸酶活性，这对于 Eya/Six1 复合物的致癌潜力至关重要。这种磷酸酶的活性位点与大多数其他细胞磷酸酶不同，它提供了独特的靶点。我们附属大学的研究人员发现了一类新型小分子，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可以阻止 Eya/Six1 的增殖、存活和转移活动。细胞培养测定将评估这些化合物对具有中至高水平 Eya 和 Six1 的非癌性乳腺上皮细胞系和乳腺癌细胞的影响。体内测定将评估注射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，它将建立通过新方法开发治疗乳腺癌和可能其他癌症的药物的可行性。由于目标蛋白在大部分乳腺癌中过度表达，并且在正常组织中不存在或表达极少，因此这种方法可能对大量乳腺癌患者广泛有效，并且毒性较低，满足当前治疗晚期乳腺癌的需求。此外，小分子抑制剂的制造成本应该低于目前基于抗体的乳腺癌治疗药物。

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.