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（由申请人提供）：大多数抗癌药物靶向酶或蛋白质受体上的结合袋，这些药物通常靶向可以削弱肿瘤的上游通路，但在一段时间内可能无法击中肿瘤的中心节点。众所周知，转录因子可以充当这些“中心节点”。事实上，转录失调与大多数（如果不是全部）对癌细胞至关重要的特性有关，包括不受控制的生长、无限的复制潜力、迁移和迁移。但很少有人入侵。调查员 Six1 同源框基因编码对胚胎发育至关重要的转录因子，而在大多数组织中，Six1 的表达在发育完成后会被重新激活。作为 50% 的原发性乳腺肿瘤和 90% 的转移性病变，以及许多其他肿瘤类型，Six1 在乳腺癌和其他癌症的肿瘤发生、肿瘤生长和转移中发挥着因果作用，其抑制作用可显着减少肿瘤的发生。 Six1 没有内在的激活或抑制结构域，因此需要辅助因子来介导其转录作用，我们已经证明 Six1 需要 Eya 辅助因子来介导其在乳腺中的促增殖和促转移作用。对公共乳腺癌微阵列数据集的检查表明，Six1 和 Eya 的高表达水平（而不是单独的任一基因）与缩短的复发时间、缩短的转移时间以及缩短的总体时间相关。重要的是，我们最近确定了 Six1/Eya2 复合物的晶体结构，这表明 Six1 使用单个 α 螺旋与 Eya 相互作用，类似于两种众所周知的蛋白质-蛋白质相互作用（p53/HDM2 和 Bak/我们进一步证明，Six1 螺旋上的单个氨基酸突变会消除 Six1 与 Eya 的结合以及 Six1 介导的肿瘤发生和转移。该项目的目标是通过表征和优化通过使用高通量筛选鉴定的命中化合物来鉴定和开发针对 Six1/Eya 复合物的新型抗癌药物（目标 1）。所鉴定的抑制剂将在两种细胞中进行测试。由于 Six1/Eya 复合物影响致瘤和转移过程的多个阶段，并且在大多数成人组织中不表达，因此在培养物和动物模型中检测其抑制致瘤性和转移的能力（目标 2）。靶向复合物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 进展且副作用有限，这是大多数当前疗法无法做到的。

项目成果

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

CtBP1 在致癌过程中的作用及其作为治疗靶点的潜力。

• 发表时间: 2017
• 影响因子: 5.7
• 作者: Blevins, Melanie A;Huang, Mingxia;Zhao, Rui
• 通讯作者: Zhao, Rui