Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma

PTEN 缺陷胶质母细胞瘤中 S6 和 TAM 激酶的共同靶向

基本信息

批准号：
10308048
负责人：
David R Plas
金额：
$ 41.28万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2019-12-11 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308048
关键词：
Address Adolescence Adult Affect Age Agreement Apoptotic Autoimmunity Biological Biological Models Birth Body Size CRISPR/Cas technology Cells Clinical Trials Cohort Studies Combined Modality Therapy Data Development Embryonic Development Event FDA approved Family Family member Future Genetic Genetic Transcription Glioblastoma Glioma Growth Knock-out Ligands Link Longevity MERTK gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mammals Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Methylation Microglia Molecular Target Mus Mutation Names Neuroglia Obesity Oncology Outcome PTEN gene Pathway interactions Patients Perinatal mortality demographics Phagocytosis Pharmacologic Substance Pharmacology Phase Phenotype Pheochromocytoma Phosphorylation Phosphotransferases Physiological Prognosis Protein Kinase Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Reporting Research Resistance Ribosomal Protein S6 Kinase Sampling Signal Transduction Solid System TYRO3 gene Technology Testing The Cancer Genome Atlas Therapeutic Tumor Suppressor Proteins Tumor-Derived Tyrosine Tyrosine Kinase Inhibitor Up-Regulation Validation Work cBioPortal cell type crizotinib cytotoxic cytotoxicity drug development experimental study genetic analysis genetic approach genome editing hematopoietic tissue inhibitor leukemia macrophage member neoplastic cell paralogous gene patient derived xenograft model programs promoter protein kinase inhibitor response targeted treatment tumor tumor growth tumor metabolism

项目摘要

Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma Project Summary The ribosomal S6 protein kinases (S6Ks) are activated in response to loss of the tumor suppressor PTEN in glioblastoma and other cancers of solid and hematopoietic tissues. We previously reported that genetic inactivation of S6K1 counteracts the metabolic and anti-apoptotic effects of PTEN loss in cancer, in agreement with several observations in comparable settings. Recently we investigated pharmacological inhibitors that target S6K1, which led to the identification of a PTEN-specific vulnerability to combination inhibition of S6K1 together with the TAM family of tyrosine kinases. The TAM family of tyrosine is named for its members, which are TYRO3, AXL, and MERTK. TAM tyrosine kinases are highly targetable in oncology, as there are several late-stage clinical trial and FDA-approved tyrosine kinase inhibitors that have activity against all three members. In a validation phase using genetic approaches to investigate the requirements for PTEN-selective cytotoxicity, results revealed that inactivation of TAM kinases is sufficient to sensitize PTEN-deficient cells to inhibition of S6K1. In the present research application, we propose to extend the genetic analysis of S6 and TAM kinases to elucidate the mechanisms that relate the kinases in the setting of PTEN-deficient glioblastoma. Experiments will make use of CRISPR Cas9 genome editing technologies to inactivate the S6K and TAM kinase family members, alone or in combination, while determining signaling and metabolic effects. Model systems will employ patient-derived tumor samples to assess the generality and applicability of genetic results to physiologic functions of glioblastoma tumors/cells. We anticipate that the results will provide the mechanistic framework that will inform the development of targeted therapeutic strategies affecting the S6Ks and TAMs themselves, or signaling components that are part of their pathways.

在缺乏PTEN的胶质母细胞瘤中共同靶向S6和TAM激酶项目摘要核糖体S6蛋白激酶（S6K）因响应于肿瘤抑制剂PTEN的损失而激活固体和造血组织的胶质母细胞瘤和其他癌症。我们以前报道了遗传 S6K1的失活抵消了PTEN损失在癌症中的代谢和抗凋亡作用，一致在可比较的设置中进行了几个观察。最近，我们调查了药理学抑制剂靶S6K1，这导致鉴定了PTEN特异性脆弱性S6K1的组合抑制与Tam家族的酪氨酸激酶一起。 TAM的酪氨酸家族以其成员的名字命名是Tyro3，Axl和Mertk。 TAM酪氨酸激酶在肿瘤学上是高度靶向的，因为有几个后期临床试验和FDA批准的酪氨酸激酶抑制剂，对这三种成员。在验证阶段，使用遗传方法研究PTEN选择性的需求细胞毒性，结果表明，TAM激酶的失活足以使缺乏PTEN缺陷的细胞对抑制S6K1。在本研究应用中，我们建议扩展S6和S6的遗传分析 TAM激酶阐明了在缺乏PTEN缺乏胶质母细胞瘤的情况下与激酶相关的机制。实验将利用CRISPR CAS9基因组编辑技术使S6K和TAM失活激酶家庭成员，单独或组合，同时确定信号传导和代谢作用。模型系统将采用患者来源的肿瘤样本来评估遗传结果的普遍性和适用性胶质母细胞瘤肿瘤/细胞的生理功能。我们预计结果将提供机械框架将为有针对性的治疗策略的发展提供影响S6KS的制定和tams本身或信号成分是其路径的一部分。