Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma

靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法

基本信息

批准号：
10228075
负责人：
Daniela Annenelie Bota
金额：
$ 41.17万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10228075
关键词：
Adult Animal Model Apoptosis Automobile Driving Binding Biochemical Bioenergetics Biogenesis Biological Biology Blood - brain barrier anatomy Brain Brain Neoplasms CRISPR/Cas technology Cell Culture Techniques Cell Cycle Cell Death Cell Line Cell Survival Cells Cervical Chemotherapy and/or radiation Clinical Trials Colorectal Cancer Cues DNA biosynthesis Development Disease Drug Targeting Equilibrium Excision FDA approved Glioblastoma Glioma Goals Growth Heat shock proteins Homeostasis Human Hypoxia Immunodeficient Mouse In Vitro Inbred BALB C Mice Knock-out Lead Libraries Link Malignant Glioma Malignant Neoplasms Maximum Tolerated Dose Measures Mesenchymal Metabolic Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Molecular Chaperones Neoplasm Metastasis Normal Cell Operative Surgical Procedures Oral Pathway interactions Patients Peptide Hydrolases Pharmacology Phenotype Primary Brain Neoplasms Process Prognosis Prognostic Factor Proteins Publishing RNA Radiation Radiation therapy Recurrence Regulation Resistance Respiration Role Small Interfering RNA Structure-Activity Relationship Study models Survival Rate System Testing Therapeutic Toxic effect Up-Regulation Xenograft Model anti-cancer base chemotherapeutic agent chemotherapy clinical application cytotoxic endopeptidase La epithelial to mesenchymal transition gene therapy glioma cell line in vivo in vivo Model inhibitor/antagonist interest knock-down melanoma mitochondrial DNA mutation mitochondrial dysfunction mitochondrial metabolism novel novel strategies novel therapeutics nutrient deprivation overexpression protein degradation response small molecule stable cell line standard of care stem cells stem-like cell synergism temozolomide therapy resistant tumor tumor growth

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is the most aggressive primary brain tumor with a two years survival rate of less than 50% following surgical resection, radiation, and chemotherapy. Recurrence is nearly universal after the first-line treatment, and there is currently no therapy proven to prolong survival after tumor recurrence. Thus, there is an urgent need for more effective GBM therapies. The overarching goal of this project is to further develop and validate new chemotherapeutic agents for the treatment of GBM. GBM's resistance to radiation and chemotherapy heavily correlates with extensive hypoxia-induced, mitochondria-dependent phenotypic changes such as glycolytic respiration, decreased the ability to undergo apoptosis and extensive invasiveness. Mitochondrial LonP1 is an ATP-stimulated protease, directly up-regulated by HIF-1α. LonP1 is overexpressed in human malignant gliomas and its elevated expression levels are associated with high glioma tumor grade and poor patient survival. Therefore, regulation of mitochondrial function by inhibiting LonP1 protease could represent a novel approach for GBM and potentially other fast-growing malignancies which heavily depend on hypoxic adaptation. The proposed project is based on our published and preliminary results obtained from in vitro (cell- based) studies with LonP1 inhibition using siRNA and the inhibitor compounds CC4 and BT317 and in vivo LonP1-overexpression xenograft models studies. BT317 is a small molecule compound, able to cross the blood- brain barrier and to achieve promising concentrations in the brain. BT317 is highly effective in inducing cell death in multiple glioma lines and patient-derived glioblastoma stem cell cultures, with an IC50 value of 60-100 µM (temozolomide – the main FDA approved therapy and has minimal toxicity in normal lines. identifying BT317 as a potentially new therapy for this universally fatal disease. In this project, we propose to: (1) examine the effect of mitochondrial LonP1 knockout in distinct patient-derived primary glioma stem-like cells (GSC), glioblastoma cell lines and xenograft models, (2) identify microenvironment cues and LonP1-induced mitochondrial changes that drive GSC invasiveness, and (3) examine the drug-target inhibition and molecular mechanisms for anti- cancer efficacy of the LonP1 inhibitor, BT317. The studies outlined here are the first to explore a very promising avenue – mitochondrial Lon protease inhibition – as a treatment for GBM.

项目摘要胶质母细胞瘤（GBM）是最具侵略性的原发性脑肿瘤，生存率小于50％手术切除，放射线和化学疗法。在第一线之后，复发几乎是普遍的治疗，目前尚无疗法证明可以延长肿瘤复发后的生存率。那有一个迫切需要更有效的GBM疗法。该项目的总体目标是进一步发展和验证用于治疗GBM的新化学治疗剂。 GBM对辐射的抵抗力和化学疗法与广泛的缺氧诱导的线粒体依赖性表型变化密切相关例如糖酵解呼吸，降低了凋亡和广泛侵入性的能力。线粒体LONP1是ATP刺激的蛋白酶，直接由HIF-1α上调。 LONP1过表达人类恶性神经胶质瘤及其表达水平升高与高神经胶质瘤肿瘤级相关，患者生存不佳。因此，通过抑制LONP1蛋白酶来调节线粒体功能可以代表 GBM的一种新型方法以及可能严重依赖低氧的其他快速增长的恶性肿瘤适应。拟议的项目是基于我们从体外获得的发表的初步结果（细胞 - 基于）使用siRNA和抑制剂化合物CC4和BT317和体内抑制剂抑制作用的研究 LONP1 - 超级表达模型研究。 BT317是一种小分子化合物，能够越过血液脑屏障并达到大脑中的承诺浓度。 BT317在诱导的细胞死亡中非常有效在多个神经胶质瘤线和患者来源的胶质母细胞瘤干细胞培养物中，IC50值为60-100 µm （替莫唑胺 - 主要FDA批准的疗法，在正常线上的毒性最小。将BT317识别为这种普遍致命疾病的潜在新疗法。在这个项目中，我们建议：（1）检查效果在不同患者衍生的原发性神经胶质瘤干细胞（GSC），胶质母细胞瘤中线粒体LONP1敲除细胞系和异种移植模型，（2）识别微环境线索和LONP1诱导的线粒体变化这驱动GSC的侵入性，（3）检查药物目标抑制和分子机制 LONP1抑制剂的癌症效率，BT317。这里概述的研究是第一个探索一个非常有希望的研究大道 - 线粒体LON蛋白酶抑制 - 作为GBM的治疗方法。