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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：
9887655
负责人：
David R Plas
金额：
$ 43.44万
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/9887655
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 Modeling 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 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/antagonist leukemia macrophage member neoplastic cell outcome forecast paralogous gene 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.

共同靶向S6和TAM激酶治疗pten缺陷胶质母细胞瘤