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.

抽象的当前的乳腺癌治疗主要基于靶向治疗。特别是激素治疗靶标 ER阳性癌症中的雌激素受体（ER），而过表达HER2的癌症则用不同类型的HER2靶向药物。后者包括单克隆抗体，小分子抑制剂或 HER2-抗体结合到细胞毒性药物中。乳腺癌治疗中使用的其他靶向药物 CDK4/6，MTOR，EGFR，HDAC或PARP。不幸的是，许多患者对靶向疗法没有反应或最初负责，然后是发展抵抗力。鉴定致癌的新“可药”介体当前的乳腺癌药物靶标的影响可能会在癌症治疗方面产生临床改善对靶向治疗有抵抗力。本质上所有信号转导途径的常见终点由癌症药物靶标介导的对调节肿瘤生长，存活和的基因转录的影响转移。转录空间中最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。这些激酶的抑制剂正在进行临床前和临床发展。我们假设转录调节的抑制剂激酶将与用于治疗乳腺癌的靶向药物协同作用，并结合靶向药物使用转录调节激酶抑制剂可能会克服或阻止发展靶向药物。我们已经确定了靶向乳腺癌药物和转录调节激酶抑制剂，最值得注意的是CDK8/19抑制剂与ER和ER和 HER2靶向药物和CDK7抑制剂含有EGFR靶向药物。在项目的剩余期间，我们将描述发现的组合的最潜力，即HER2和 CDK8/19抑制剂。在AIM 1下，HER2抑制剂Lapatinib与A之间的组合效率 CDK8/19抑制剂将在体内进行测试，使用Lapatinib敏感和抗性HER2-的Xenogroticon模型阳性乳腺癌细胞。目标2是研究拉帕替尼和 CDK8/19抑制剂。此目的的实验计划是基于RNA-seq分析的结果，确定了这种协同作用的候选候选者。这些候选基因的表达受调节通过转录因子，其磷酸化取决于CDK8/19和HER2。目标3是在抗HER2单克隆抗体和潜在的CDK8/19抑制剂之间开发共轭物，并测试相对于未结合的剂，该共轭物的体外效率。这个项目的成功将铺路通过新颖的组合来提高针对性治疗在乳腺癌中的效率的方式当前具有转录调节激酶抑制剂的靶向药物。未来的基础和翻译研究 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靶向HER2靶向药物具有抗性的转移性HER2阳性乳腺癌。