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：
10535467
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/10535467
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 Macrophage Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mammals Mediating Mediator 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 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 Tyrosine Tyrosine Kinase Inhibitor Up-Regulation Validation Work cBioPortal cell type crizotinib cytotoxic cytotoxicity drug development efficacy evaluation experimental study genetic analysis genetic approach genome editing hematopoietic tissue inhibitor leukemia member paralogous gene patient derived xenograft model pharmacologic 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.

PTEN 缺陷胶质母细胞瘤中 S6 和 TAM 激酶的共同靶向项目概要核糖体 S6 蛋白激酶 (S6K) 在肿瘤抑制因子 PTEN 缺失时被激活胶质母细胞瘤和其他实体和造血组织癌症。我们之前报道过，遗传 S6K1 失活抵消了癌症中 PTEN 缺失的代谢和抗凋亡作用，这一点与此一致在可比较的环境中进行了多次观察。最近我们研究了药理学抑制剂目标 S6K1，这导致鉴定出 PTEN 特异的对 S6K1 组合抑制的脆弱性与酪氨酸激酶 TAM 家族一起。酪氨酸 TAM 家族以其成员命名，其中是 TYRO3、AXL 和 MERTK。 TAM 酪氨酸激酶在肿瘤学中具有高度针对性，因为有多种后期临床试验和 FDA 批准的酪氨酸激酶抑制剂对这三种药物均具有活性成员。在验证阶段，使用遗传方法来研究 PTEN 选择性的要求细胞毒性，结果表明 TAM 激酶失活足以使 PTEN 缺陷细胞对 S6K1 的抑制。在目前的研究应用中，我们建议扩展 S6 和 TAM 激酶阐明 PTEN 缺陷性胶质母细胞瘤中激酶的相关机制。实验将利用 CRISPR Cas9 基因组编辑技术来灭活 S6K 和 TAM 激酶家族成员单独或组合，同时确定信号传导和代谢效应。模型系统将采用源自患者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制框架将为影响 S6K 的靶向治疗策略的制定提供信息和 TAM 本身，或作为其途径一部分的信号成分。