Developing cancer therapies through targeting the Six1/Eya transcriptional complex

通过靶向 Six1/Eya 转录复合物开发癌症疗法

• 批准号: 8989081
• 负责人: Heide L. Ford
• 金额: $ 20.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-18 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989081
• 关键词: Adult; Adverse effects; Amino Acids; Animal Model; Antineoplastic Agents; Apoptosis; Binding; Breast; Breast Cancer Cell; Breast cancer metastasis; Cell Culture Techniques; Cells; Characteristics; Complex; Data; Data Set; Development; Disease Progression; Drug Targeting; Embryonic Development; Enzymes; Genes; Genetic Transcription; Goals; Growth; Health; Homeobox Genes; Immune; Immunocompromised Host; Lead; MDM2 gene; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Molecular; Mutation; Neoplasm Metastasis; Oncogenic; Organ; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Primary Neoplasm; Property; Proteins; RNA Interference; Relapse; Repression; Research Personnel; Role; Signal Transduction; Specificity; Staging; Stimulus; Structure; TP53 gene; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Tumor Volume; Tumorigenicity; Xenograft procedure; alpha helix; cancer cell; cancer microarray; cancer therapy; cancer type; cofactor; epithelial to mesenchymal transition; high throughput screening; inhibitor/antagonist; malignant breast neoplasm; metastatic process; migration; mouse model; novel; novel anticancer drug; organ growth; overexpression; protein protein interaction; receptor; small molecule; transcription factor; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Most anti-cancer drugs target binding pockets in enzymes or on protein receptors. These drugs often target upstream pathways that can cripple tumors, but may fail to hit the central node of the tumor. For some time, it has been known that transcription factors can serve as these "central nodes". Indeed, de-regulated transcription has been associated with most, if not all, properties that are critical to the cancer cell, including uncontrolled growth, unlimited replicative potential, migration and invasion. Yet few investigators have taken on the more difficult task of targeting transcription factors. The Six1 homeobox gene encodes a transcription factor that is critical for embryonic development. In most tissues, Six1 expression is lost once development is complete. However, Six1 is re-activated in as many as 50% of primary breast tumors and 90% of metastatic lesions, as well as in many other tumor types. Six1 plays a causal role in tumor initiation, tumor growth, and metastasis of breast and other cancers, and its inhibition dramatically diminishes the aforementioned properties in several mouse models of cancer. Six1 has no intrinsic activation or repression domains, and thus requires cofactors to mediate its transcriptional effects. We have demonstrated that Six1 requires the Eya cofactor to mediate its pro-proliferative and pro-metastatic effects in breast cancer cells. Examination of public breast cancer microarray datasets reveals that high expression levels of Six1 and Eya together, but not either gene alone, correlate with shortened time to relapse, shortened time to metastasis, and shortened overall survival in breast cancer. Importantly, we recently determined the crystal structure of the Six1/Eya2 complex, which reveals that Six1 uses a single alpha helix to interact with Eya, resembling two well-known protein- protein interactions (p53/HDM2 and Bak/Bcl-xL) that have been successfully targeted by small molecules. We further demonstrated that a single amino acid mutation on the Six1 helix abrogates the binding of Six1 to Eya and Six1-mediated tumor initiation and metastasis. The goal of this project is to identify and develop novel anti- cancer agents that target the Six1/Eya complex through characterizing and optimizing hit compounds identified through the use of a high throughput screen (Aim 1). Identified inhibitors will be tested in both cell culture and animal models for their ability to inhibit tumorigenicity and metastasis (Aim 2). Since the Six1/Eya complex influences multiple stages of the tumorigenic and metastatic processes and is not expressed in most adult tissues, targeting this never before targeted complex has the therapeutic potential to inhibit breast and other cancers both at early and later stages of disease progression with limited side effects, something most current therapies do not do.

 描述(申请人提供)：大多数抗癌药物针对的是酶或蛋白质受体上的结合口袋。这些药物通常针对的是可以削弱肿瘤的上游通路，但可能无法击中肿瘤的中心结节。一段时间以来，人们就知道转录因子可以充当这些“中心节点”。事实上，转录失控与癌细胞的大多数(如果不是全部)特性有关，包括不受控制的生长、无限的复制潜力、迁移和侵袭。然而，很少有调查人员 已经承担了针对转录因子的更困难的任务。SIX1同源框基因编码一种对胚胎发育至关重要的转录因子。在大多数组织中，一旦发育完成，SIX1的表达就会丢失。然而，SIX1在多达50%的原发乳腺肿瘤和90%的转移性病变以及许多其他类型的肿瘤中被重新激活。SIX1在乳腺癌和其他癌症的肿瘤起始、肿瘤生长和转移中起着因果作用，它的抑制在几种癌症小鼠模型中显著降低了上述特性。SIX1没有内在的激活或抑制结构域，因此需要辅因子来调节其转录效应。我们已经证明，SIX1需要Eya辅因子来介导其在乳腺癌细胞中的促增殖和促转移作用。对公共乳腺癌微阵列数据集的研究表明，SIX1和EYA的高表达水平一起，而不是其中任何一个基因的单独表达，与乳腺癌复发时间、转移时间和总生存期的缩短相关。重要的是，我们最近测定了SIX1/Eya2复合体的晶体结构，揭示了SIX1使用单个α螺旋与Eya相互作用，类似于两种著名的蛋白质-蛋白质相互作用(P53/Hdm2和Bak/Bclxl)，这两种作用已经成功地被小分子靶向。我们进一步证明，SIX1螺旋上的一个单一氨基酸突变取消了SIX1与Eya和SIX1介导的肿瘤起始和转移的结合。该项目的目标是通过使用高通量筛选(目标1)来表征和优化HIT化合物，从而识别和开发以SIX1/EYA复合体为靶点的新型抗癌药物。已确定的抑制剂将在细胞培养和动物模型中进行测试，以确定它们抑制肿瘤形成和转移的能力(目标2)。由于SIX1/EYA复合体影响肿瘤发生和转移过程的多个阶段，并且在大多数成人组织中不表达，靶向这种以前从未靶向的复合体具有在疾病早期和晚期抑制乳腺癌和其他癌症的治疗潜力 进展和有限的副作用，这是大多数目前的治疗方法所不能做到的。

项目成果

The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target.

• DOI: 10.1158/1535-7163.mct-16-0592
• 发表时间: 2017-06
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Blevins MA;Huang M;Zhao R
• 通讯作者: Zhao R