Potentiating targeted drugs in breast cancer via transcription-regulating kinases

通过转录调节激酶增强乳腺癌靶向药物

基本信息

批准号：
9794385
负责人：
Eugenia V Broude
金额：
$ 22.35万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794385
关键词：
Advisory Committees Antibodies Antibody-drug conjugates Antineoplastic Agents Area Basic Science Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast Cancer therapy CDK4 gene Candidate Disease Gene Cells Centers of Research Excellence Chromatin Clinical Clinical Trials Collaborations Cyclin-Dependent Kinases Cytotoxic agent Disease Drug Combinations Drug Synergism Drug Targeting Drug usage ERBB2 gene Epidermal Growth Factor Receptor Estrogen Receptors Estrogen receptor positive FRAP1 gene Family Future Gene Expression Genes Genetic Transcription Goals Grant Histone Deacetylase Knock-out Malignant Neoplasms Mediating Mediator of activation protein MicroRNAs Molecular Monoclonal Antibodies Neoplasm Metastasis Oncogenic Patients Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Proteins Research Resistance Resistance development Role STAT1 gene STAT3 gene Signal Transduction Pathway Testing Therapeutic Therapeutic Effect Translational Research Trastuzumab Tumor Suppressor Genes Xenograft Model advanced breast cancer antibody conjugate base cancer therapy clinical development combinatorial drug discovery drug synthesis hormone therapy improved in vitro testing in vivo in vivo evaluation inhibitor/antagonist kinase inhibitor knock-down lapatinib malignant breast neoplasm novel overexpression preclinical development prevent small hairpin RNA small molecule inhibitor success synergism targeted treatment therapy resistant transcription factor transcriptome sequencing tumor tumor growth

项目摘要

ABSTRACT Current breast cancer therapy is largely based on targeted therapeutics. In particular, hormonal therapy targets the estrogen receptor (ER) in ER-positive cancers, whereas cancers that overexpress HER2 are treated with different types of HER2-targeted drugs. The latter include monoclonal antibodies, small molecule inhibitors, or HER2-antibodies conjugated to a cytotoxic drug. Other targeted drugs used in breast cancer therapy act on CDK4/6, mTOR, EGFR, HDAC or PARP. Unfortunately, many patients do not respond to targeted therapies or respond initially and then develop resistance. Identification of new “druggable” mediators of the oncogenic effects of the current breast cancer drug targets could yield clinical improvements in the treatment of cancers resistant to targeted therapy. The common endpoint of essentially all the signal transduction pathways mediated by cancer drug targets is an effect on transcription of genes that regulate tumor growth, survival and metastasis. The most targetable proteins in the transcription space are transcription-regulating kinases belonging to the cyclin-dependent kinase (CDK) family, CDK7, CDK8/19 and CDK9. Inhibitors of these kinases are undergoing preclinical and clinical development. We hypothesize that inhibitors of transcription-regulating kinases will synergize with targeted drugs used to treat breast cancer, and that combinations of targeted drugs with transcription-regulating kinase inhibitors may overcome or prevent the development of resistance to targeted drugs. We have identified several synergistic combinations of targeted breast cancer drugs and transcription-regulating kinase inhibitors, most notably the combinations of CDK8/19 inhibitors with ER- and HER2-targeting drugs and CDK7 inhibitors with EGFR-targeting drugs. In the remaining period of the project, we will characterize the most potent of the discovered combinations, namely a combination of HER2 and CDK8/19 inhibitors. Under Aim 1, the efficacy of a combination between HER2 inhibitor lapatinib and a CDK8/19 inhibitor will be tested in vivo, using xenograft models of lapatinib-sensitive and resistant HER2- positive breast cancer cells. Aim 2 is to investigate the mechanism of the synergy between lapatinib and CDK8/19 inhibitors. The experimental plan for this Aim is based on the results of RNA-Seq analysis that identified candidate downstream mediators of this synergy. Expression of these candidate genes is regulated by transcription factors, phosphorylation of which is dependent on both CDK8/19 and HER2. Aim 3 is to develop a conjugate between an anti-HER2 monoclonal antibody and a potent CDK8/19 inhibitor and to test the in vitro efficacy of this conjugate, relative to the unconjugated agents. The success of this project will pave the way towards improving the efficacy of targeted therapy in breast cancer through novel combinations of the current targeted drugs with transcription-regulating kinase inhibitors. Future basic and translational research on the combinatorial effects of HER2- and CDK8/19-targeted drugs may have a profound impact on the treatment of metastatic HER2-positive breast cancers that are resistant to HER2-targeted drugs.

抽象的目前的乳腺癌治疗主要基于靶向治疗，特别是激素治疗目标。 ER 阳性癌症中的雌激素受体 (ER)，而过度表达 HER2 的癌症则采用不同类型的 HER2 靶向药物包括单克隆抗体、小分子抑制剂或与细胞毒性药物结合的 HER2 抗体可作用于乳腺癌治疗。不幸的是，许多患者对靶向治疗或 PARP 没有反应。最初产生反应，然后产生抗性，鉴定出新的“可成药”致癌介质。当前乳腺癌药物靶标的效果可能会改善癌症治疗的临床效果基本上所有信号转导途径的共同终点。由癌症药物靶标介导的作用是对调节肿瘤生长、存活和生存的基因转录产生影响。转录空间中最可靶向的蛋白质是转录调节激酶。属于细胞周期蛋白依赖性激酶 (CDK) 家族，CDK7、CDK8/19 和 CDK9 的抑制剂。我们正在进行临床前和临床开发。激酶将与用于治疗乳腺癌的靶向药物产生协同作用，并且靶向药物的组合与转录调节激酶抑制剂一起使用可以克服或预防耐药性的发展我们已经确定了几种靶向乳腺癌药物和的协同组合。转录调节激酶抑制剂，最值得注意的是 CDK8/19 抑制剂与 ER- 和 HER2靶向药物和CDK7抑制剂与EGFR靶向药物在项目的剩余时间内，我们将描述已发现的最有效的组合，即 HER2 和 CDK8/19 抑制剂在目标 1 下，HER2 抑制剂拉帕替尼与一种药物联合使用的功效。 CDK8/19抑制剂将使用拉帕替尼敏感和耐药的HER2异种移植模型进行体内测试目的2是研究拉帕替尼和阳性乳腺癌细胞之间的协同作用机制。 CDK8/19 抑制剂该目标的实验计划基于 RNA-Seq 分析的结果：确定了这种协同作用的候选下游介质，这些候选基因的表达受到调节。转录因子的磷酸化依赖于 CDK8/19 和 HER2，目的是开发抗 HER2 单克隆抗体和强效 CDK8/19 抑制剂之间的缀合物并进行测试该缀合物相对于未缀合药物的体外功效将为该项目的成功铺平道路。通过新的组合来实现乳腺癌靶向治疗的功效目前的靶向药物与转录调节激酶抑制剂的未来基础和转化研究。 HER2和CDK8/19靶向药物的组合作用可能对治疗产生深远的影响对 HER2 靶向药物耐药的转移性 HER2 阳性乳腺癌。