Kinase Inhibition in Kidney Cancer

肾癌中的激酶抑制

基本信息

批准号：
9176328
负责人：
WILLIAM Y. KIM
金额：
$ 43.24万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-02 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176328
关键词：
Cell Line Characteristics Chemicals Clear Cell Clinical Combined Modality Therapy Cytotoxic Chemotherapy Dasatinib Endothelial Growth Factors Receptor FDA approved FRAP1 gene Family Genetic Transcription Genome Genomics Heterogeneity Histologic Human In Vitro Incidence Janus kinase Lead Malignant Epithelial Cell Mass Spectrum Analysis Molecular Biology Molecular Profiling Mutation Pathway interactions Patients Phosphotransferases Play Protein Tyrosine Kinase Proteomics RNA Renal Cell Carcinoma Renal carcinoma Resistance Role Running SDZ RAD Signal Transduction Signal Transduction Pathway TYK2 Testing Therapeutic Time United States Validation Vascular Endothelial Growth Factors Work Xenograft Model Xenograft procedure base combinatorial high throughput screening in vivo inhibitor/antagonist innovative technologies member neoplastic cell novel predictive marker response targeted treatment therapy development tumor tumor xenograft

项目摘要

ABSTRACT The incidence of renal cell carcinoma (RCC) is on the rise. 65,000 new cases occur annually in the United States. Vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) inhibitors are FDA approved and commonly used treatments for advanced RCC but result in increases in overall survival by only months. At this time, the most druggable portion of the genome remains the kinome. Through unbiased, high-throughput screening we have identified and validated the therapeutic value of a novel kinase in RCC, tyrosine kinase 2 (TYK2: a member of the Janus Kinase family) and demonstrate that it plays a role in mTOR inhibitor resistance. We have characterized a signaling network in which TYK2 positively regulates the SRC family kinases (SFKs) and demonstrate that dual inhibition of mTOR and SRC with everolimus and dasatinib induces tumor regression in vivo. Based on these results we hypothesize that inhibition of the TYK2/SRC axis is a tractable therapeutic strategy in a subset of RCC, that we can define predictive markers of TYK2/SRC inhibitor response, and that defining the kinomic landscape of RCC and its response to mTOR inhibition will lead to further combinatorial targets.

抽象的肾细胞癌（RCC）的发生率正在上升。美国联合每年发生65,000例新案件国家。雷帕霉素（MTOR）的血管内皮生长因子受体（VEGFR）和哺乳动物靶标抑制剂是FDA批准的，并且常用用于晚期RCC的治疗方法，但导致增加总体生存仅数月。目前，基因组中最有吸毒的部分仍然是Kinome。通过公正的高通量筛选，我们已经确定并验证了新颖的治疗价值 RCC中的激酶，酪氨酸激酶2（Tyk2：Janus激酶家族的成员），并证明它扮演着一个在MTOR抑制剂耐药性中的作用。我们表征了一个信号网络，其中TYK2积极调节SRC家族激酶（SFK），并证明对MTOR和SRC的双重抑制依维莫司和达沙替尼在体内诱导肿瘤回归。基于这些结果，我们假设 TYK2/SRC轴的抑制是RCC子集中的可拖动治疗策略，我们可以定义 TYK2/SRC抑制剂响应的预测标记，以及定义RCC及其ITS的激光景观对MTOR抑制作用的反应将导致进一步的组合靶标。