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Targeting therapeutic resistance in glioblastoma

靶向胶质母细胞瘤的治疗耐药性

基本信息

批准号：
10588313
负责人：
NATASHA Y FRANK
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588313
关键词：
Afghanistan Angiogenesis Inhibitors Apoptosis Apoptotic Binding Blood - brain barrier anatomy Brain Neoplasms Cancer Control Cancer Etiology Cell Cycle Arrest Cell Cycle Regulation Cell Maintenance Cell membrane Cell physiology Cessation of life Clinical Colon Carcinoma Colorectal Cancer DDR1 gene DNA DNA Repair Development Drug resistance Enhancers Epigenetic Process Epithelium Etiology Evolution Excision Exposure to Feedback G2/M Arrest General Population Genes Glioblastoma Heterogeneity Human Immunotherapeutic agent Impairment Incidence Interruption Invaded Iraq Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator Membrane Membrane Proteins Mesenchymal Military Personnel Modality Monoclonal Antibodies Multi-Drug Resistance Nature Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures PI3K/AKT PIK3CG gene Pathway interactions Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Physiological Primary carcinoma of the liver cells Production Prognosis Quality of life Radiation Receptor Protein-Tyrosine Kinases Recurrence Refractory Regulation Repression Resistance Signal Pathway Signal Transduction Testing Therapeutic Toxicant exposure Tumor Stem Cells United States Vascular Endothelial Growth Factor Receptor-1 Veterans Vietnam active duty agent orange angiogenesis axl receptor tyrosine kinase burn pit cancer stem cell chemotherapy clinically relevant epigenetic regulation epigenome improved in vitro Model in vivo inorganic phosphate knockout gene leukemia malignant breast neoplasm malignant mouth neoplasm melanoma member neoplastic cell new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics phosphatidylinositol receptor pluripotency receptor recruit refractory cancer response self-renewal stem cell biomarkers stem cell self renewal stem cells success targeted treatment temozolomide therapy resistant tumor tumor growth tumor heterogeneity tumor progression tumor-immune system interactions

项目摘要

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with extremely poor prognosis and survival. Although relatively rare in the US general population, GBM is the third most common cause of cancer death in the US active-duty military. The relatively transient nature of clinical responses to currently available therapies underlines the urgency for the development of additional therapeutic strategies. Multiple studies have demonstrated the existence of aggressive cancer stem cell (CSC) subpopulations in GBM and characterized their contribution to GBM progression, therapeutic resistance and recurrence; however, efforts to eliminate or functionally modulate these therapy-refractory subpopulations have thus far met with limited success. ATP-binding cassette, sub-family B (MDR/TAP), member 5 (ABCB5), an integral plasma membrane protein first cloned and characterized by the applicant (Frank et al. J Biol Chem. 2003), is highly expressed by normal tissue-specific stem cells and CSCs in several malignancies, including GBM. ABCB5 is expressed in primary GBM tumors, in which its expression is significantly correlated with the CSC marker CD133 and with overall poor survival (Lee et al. J Biol Chem. 2020). In GBM-CSCs, ABCB5 has been shown to mediate clinically relevant drug resistance to temozolomide (TMZ). ABCB5 blockade inhibited CD133-positive GBM- CSC self-renewal and abrogated TMZ-induced G2/M arrest. Recently, the applicant identified a novel critical anti-apoptotic function of ABCB5 required for normal stem cell maintenance (Ksander et al. Nature 2014) and, as a corollary, for CSC-driven tumor growth, invasion and therapeutic resistance, involving, in part, ABCB5- dependent regulation of signal transduction of the RTK AXL (Guo et al., J Biol Chem. 2018). Importantly, the applicant’s most recent preliminary studies further revealed that ABCB5 serves as a novel receptor for Phosphatidylinositol 4,5-bisphosphate (PIP2), with ABCB5/PIP2 binding shown to be required for PIP3 phosphorylation. PIP2-derived PIP3 serves as a critical mediator of receptor tyrosine kinase (RTK) signaling, and hence activation of the downstream PI3K/AKT signaling cascade. Remarkably, inhibition of ABCB5-PIP2 binding through ABCB5 monoclonal antibody blockade or ABCB5 gene knockout (KO) inhibits PIP2 phosphorylation, blocks PIP3 production and interrupts down-stream pAKT activation of the PI3K/pAKT signaling pathway, impairing RTK signal transduction on ABCB5-positive GBM-CSC. Based on this newly identified central mechanism, we hypothesize that ABCB5 is critically required for multiple RTK-dependent functions in human GBM, including stem cell-intrinsic self-renewal, anti-apoptotic, pro-angiogenic and invasive capacities, and stem cell-driven epigenetic evolution and therapeutic resistance associated cell cycle arrest (Lee et al. J Biol Chem. 2020). The proposed studies will further support the development of ABCB5 as a novel therapeutic target in GBM and should pave the way to successful eradication of ABCB5_positive GBM stem cells in human patients for improved clinical therapy.

多形性胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤，预后极差