权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

YEAST CELL-BASED SCREEN FOR BREAST CANCER THERAPEUTICS

用于乳腺癌治疗的酵母细胞筛选

基本信息

批准号：
6038194
负责人：
GRANT A. BITTER
金额：
$ 9.78万
依托单位：
BITTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-05 至 2002-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6038194
关键词：
Saccharomyces cerevisiae antineoplastics breast neoplasms cyclins drug screening /evaluation estrogen receptors genetic strain high throughput technology protein protein interaction reporter genes

项目摘要

The majority of human breast cancers express estrogen receptor alpha (ER+ phenotype). Although adjuvant treatment with tamoxifen reduces tumor recurrence and increases survival in approximately 60% of these patients, prolonged use invariably leads to resistance. For the 40% of hormone independent ER+ breast cancers, as well as the ER+ tamoxifen resistant metastases, effective therapeutics are currently lacking. Recently, a novel mechanism of activating estrogen receptor alpha (ER) was elucidated. Cyclin D1 was shown to stimulate the in vivo transcription of reporter genes activated by the ER. This stimulation by cyclin D1 occurred independently of CDK4, the ER was not phosphorylated and, importantly, reporter gene activation occurred in the absence of estrogen. It had previously been well documented that cyclin D1 is overexpressed in approximately 50% of all breast cancers. Therefore, expression of growth response genes mediated by cyclin D1/ER may be involved in the proliferation of hormone independent, ER+ breast cancers and tamoxifen resistant metastases. Compounds which inhibit transcriptional activation of genes by cyclin D1/ER may therefore prevent proliferation of these breast cancer cells. During Phase I research, Saccharomyces cerevisiae yeast strains in which reporter genes are activated by human cyclin D1/ER will be developed. This technology will be utilized in high-throughput screening programs during Phase II. Compounds discovered in such screens may be developed into effective therapeutics for hormone independent breast cancers. PROPOSED COMMERCIAL APPLICATIONS: Breast cancer is the second leading cause of cancer deaths in women in the United States, and the leading cause of cancer deaths in women aged 30 to 70 years. The technology developed during Phase I research will be used in Phase II for discovery of compounds which may be effective therapeutics for the more than 40% of ER+ breast cancers which do not respond to current endocrine therapies.

大多数人类乳腺癌表达雌激素受体α （ER+表型）。虽然他莫昔芬辅助治疗可以减少肿瘤复发并提高约60%的患者的生存率，但长期使用总是导致耐药性。对于40%的不依赖激素的ER+乳腺癌，以及ER+他莫昔芬耐药转移，目前缺乏有效的治疗方法。近年来，一种新的雌激素受体（ER）激活机制被阐明。Cyclin D1可以刺激内质网激活的报告基因的体内转录。cyclin D1的这种刺激独立于CDK4发生，内质网没有磷酸化，重要的是，报告基因激活发生在缺乏雌激素的情况下。之前有充分的文献证明，大约50%的乳腺癌中细胞周期蛋白D1过表达。因此，cyclin D1/ER介导的生长反应基因表达可能参与了激素不依赖型、ER+型乳腺癌和他莫昔芬耐药转移瘤的增殖。抑制细胞周期蛋白D1/ER基因转录激活的化合物可能因此阻止这些乳腺癌细胞的增殖。在I期研究中，将开发报告基因被人细胞周期蛋白D1/ER激活的酿酒酵母菌株。该技术将用于二期高通量筛选项目。在这种筛选中发现的化合物可能会发展成为治疗不依赖激素的乳腺癌的有效药物。拟议的商业应用：乳腺癌是美国妇女癌症死亡的第二大原因，也是30至70岁妇女癌症死亡的主要原因。在I期研究期间开发的技术将用于II期研究，以发现可能有效治疗超过40%的雌激素受体阳性乳腺癌的化合物，这些乳腺癌对目前的内分泌疗法没有反应。