Targeting Metabolic Vulnerabilities with Molecular Inhibitors of Oxidative Phosphorylation

用氧化磷酸化分子抑制剂靶向代谢脆弱性

基本信息

批准号：
10476416
负责人：
Florian Muller
金额：
$ 31.53万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476416
关键词：
Affinity Aftercare Animals Antineoplastic Agents Autopsy Binding Biochemical Biological Biology Blood - brain barrier anatomy Brain Neoplasms Cancer Science Cells Chemicals Clinical Clinical Data Clinical Trials Collection Complex Cytotoxic agent Data Deletion Mutation Dependence Dose Dose-Limiting Drug Kinetics Drug Screening Epigenetic Process Event FGFR3 gene Failure Genes Genetic Genomics Glioblastoma Glioma Gliomagenesis Glycolysis Goals Histologic Housekeeping Gene Human Hypoxia Impairment In Vitro Institutes Intracranial Neoplasms Lead Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Measures Metabolic Mitochondria Molecular Mutate Mutation Normal Cell Oncogenes Other Genetics Oxidative Phosphorylation Oxygen Consumption PTEN gene Patients Penetration Pharmaceutical Preparations Pharmacology Phosphorylation Inhibition Plasma Positron-Emission Tomography Property Radiology Specialty Recurrence Resistance Signal Transduction Solid Neoplasm Stress TACC3 gene Testing Therapeutic Toxic effect Tumor Suppressor Genes Validation Work Xenograft procedure base companion diagnostics drug response prediction enolase glioma cell line imaging agent in vivo inhibitor molecular targeted therapies mouse model mutant neoplastic cell non-invasive imaging novel novel strategies novel therapeutics patient population phase 1 testing pre-clinical precision medicine response response biomarker stem cells success targeted agent targeted treatment tool tumor tumor hypoxia tumor xenograft

项目摘要

SUMMARY: PROJECT 2 Despite unprecedented successes in many tumor types, molecular targeted therapeutics focused on targeting activated/amplified oncogenes have not had a meaningful clinical impact on patients with the incurable brain tumor glioblastoma multiforme (GBM). In this proposal we take a radically different approach to targeted therapeutics by exploiting genomic deletions, rather than mutant oncogenes, as points of selective vulnerability. Deletions create attractive therapeutic opportunities as they are usually homogenously distributed, persist during tumor recurrence, and most importantly, can expose pharmacologically targetable vulnerabilities by collaterally deleting nearby redundant metabolic housekeeping genes. We explored this concept by utilizing an unbiased chemical biology approach to identify pharmacologically targetable vulnerabilities exposed by passenger deletions. We found that inhibitors of mitochondrial oxidative phosphorylation (OxPhos) are selectively toxic to glioma cells that contained collateral homozygous deletions in the glycolytic gene ENO1. We hypothesized that the basis for this selective vulnerability is glycolysis-deficiency: ENO1-deleted glioma cells are unable to upregulate glycolysis in the face of OxPhos inhibition, a compensatory response in normal cells (Pasteur effect). A corollary of this hypothesis is that other deletions that cause glycolysis deficiency also sensitize to OxPhos inhibitors. Tool compound OxPhos inhibitors have been extensively used in in vitro studies, but are not drug-like and have poor pharmacology. MD Anderson’s Institute of Applied Cancer Science (IACS) developed a highly potent and specific OxPhos inhibitor, IACS-010759, with nM affinity for mitochondrial complex I, which readily passes the blood brain barrier and is endowed with superb pharmacological properties. In preliminary data we demonstrated that IACS-010759 destroys glycolysis-deficient glioma cells in culture and eradicates intracranial xenografts. Preliminary data indicate that the hypoxia PET probe 18F-fluoroazomycin-arabinoside (18F-FAZA) can be used as a non-invasive in vivo read-out for OxPhos inhibition (target-engagement marker for IACS- 010759), because mitochondrial oxygen consumption is a major driver of tumor-hypoxia. Based on these exceptionally encouraging pre-clinical results, we will conduct a trial of IACS-010759 on GBM patients with 18F- FAZA as a target engagement marker. The goal of this proposal is to support this trial by: 1) pre-clinically validating glycolytic-deficiency as a responder hypothesis and identifying other deletions which confer sensitivity to IACS-010759 by this mechanism, 2) validating 18F-FAZA as a non-invasive read-out for OxPhos inhibition and as a predictor of drug-response in glycolytically deficient tumors, and 3) determining target engagement (OxPhos inhibition) by 18F-FAZA and biochemical response to IACS-010759 in patients with GBMs. This proposal stands to be the first example of precision medicine for the treatment of GBMs and provides clinical validation of collateral deletions as targetable phenomena.

摘要：项目2 尽管在许多肿瘤类型中取得了前所未有的成功，但分子靶向治疗的重点是靶向激活/扩增的癌基因对无法治愈的大脑患者没有有意义的临床影响肿瘤胶质母细胞瘤多形（GBM）。在此提案中，我们采用一种完全不同的方法来定位通过利用基因组缺失而不是突变癌基因作为选择性脆弱性的疗法。删除通常会产生有吸引力的治疗机会，因为它们通常是同质分布的，在肿瘤复发，最重要的是，可以通过综合性暴露于药物的靶向脆弱性删除附近的冗余代谢管家基因。我们通过公正地探索了这个概念化学生物学方法以识别乘客暴露的药物靶向漏洞删除。我们发现线粒体氧化磷酸化（OXPHOS）的抑制剂有选择性地有毒胶质瘤细胞在糖酵解基因ENO1中包含副合同缺失。我们假设了这一点这种选择性脆弱性的基础是糖酵解缺乏症：ENO1缺失的神经胶质瘤细胞无法面对Oxphos抑制作用，正常细胞的补偿性反应（巴斯德效应）上调糖酵解。这一假设的必然是，其他导致糖酵解缺乏的缺失也对Oxphos感知抑制剂。工具化合物Oxphos抑制剂已在体外研究中广泛使用，但不是药物样并且药理学差。 MD Anderson的应用癌症科学研究所（IACS）开发了高度潜在的和特定的OXPHOS抑制剂IACS-010759，NM对线粒体复合物I的亲和力很容易通过血脑屏障，并具有出色的药物特性。在初步数据中证明IACS-010759破坏了糖酵解缺陷型神经胶质瘤细胞在培养和颅内放射素异种移植物。初步数据表明PET PET探针18F-Fluoroazomycin-Arabinoside（18F-Faza）可以用作oxphos抑制作用的无创体内读出（IACS-的目标参与标记 010759），因为线粒体氧的消耗是肿瘤 - 催眠症的主要驱动力。基于这些我们将非常令人鼓舞的临床前结果，我们将对18F-的GBM患者进行IACS-010759的试验 Faza是目标参与标记。该提案的目的是通过以下方式支持此试验验证糖酵解缺陷为响应者假设并确定其他会议敏感性的缺失通过这种机制到IACS-010759，2）将18F-FAZA验证为无创读出OXPHOS抑制和作为糖酵解不足肿瘤中药物反应的预测因子，3）确定靶标参与（OXPHOS）通过18F-FAZA的抑制作用和GBMS患者对IACS-010759的生化反应。该提议是成为治疗GBM的精确医学的第一个例子，并提供抵押删除作为可目标现象。