Multi-Modal Lysosomotropic Death Therapy for Malignant Peripheral Nerve Sheath Tu

恶性周围神经鞘多模式溶血死亡疗法 Tu

基本信息

批准号：
7651766
负责人：
Kevin A Roth
金额：
$ 24.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7651766
关键词：
Adjuvant Adverse effects Animal Cancer Model Antimalarials Apoptosis Apoptotic Autophagocytosis Caspase Caspase Inhibitor Cathepsins Cell Death Cessation of life Chloroquine Chronic Clinical Clinical Trials Complex Data Disease Enzymes FDA approved Foundations Functional disorder Future Glioblastoma Goals Human Hydroxychloroquine In Vitro Investigation Laboratories Lymphoma Lysosomes Malignant - descriptor Malignant Peripheral Nerve Sheath Tumor Mefloquine Membrane Mitochondria Modeling Molecular Mus Mutation Neoplasms Nervous system structure Neurofibromatoses Neurofibromatosis 1 Neuroglia Neurons Nude Mice Pathway interactions Patients Penetration Peripheral Nerve Sheath Positioning Attribute Prevention Property Prophylactic treatment Quinacrine Quinolone Antibiotic Regulation Reporting Resistance Solid Solubility Stress TP53 gene Testing Therapeutic Therapeutic Agents Time Transgenic Mice Transplantation Tumor Cell Line Vacuole bafilomycin A1 caspase-3 cell type chemotherapeutic agent cytotoxic effective therapy in vitro activity in vivo inhibition of autophagy insight killings lifetime risk mouse model neoplastic cell novel therapeutic intervention novel therapeutics pre-clinical prevent prophylactic public health relevance small molecule treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, rapidly fatal neoplasms for which new therapeutic approaches are desperately needed. MPNSTs occur in up to ten percent of patients with neurofibromatosis type 1 (NF1) and are highly resistant to standard chemotherapeutic agents. We have been investigating the cell death promoting activities of chloroquine (CQ), a lysosomotropic agent, for almost ten years and have found that CQ induces autophagic stress and caspase activation in a variety of normal and malignant neural cell types. We have hypothesized that CQ-induced death results from inhibition of pro- survival autophagic pathways and stimulation of both apoptotic and non-apoptotic death pathways. Importantly, CQ-induced cell death involves both p53-dependent and p53-independent pathways and given that human MPNSTs show p53 mutations or deletions in up to 75% of cases, p53-independent death pathways may be particularly critical for effective MPNST therapy. CQ has recently been reported to be a potent adjuvant to standard chemotherapeutic agents in several animal models of cancer and in the treatment of human glioblastoma multiforme (GBM) patients. Prophylactic CQ administration has also been reported to inhibit both lymphoma formation and atherosclerotic disease in transgenic mouse models of these conditions. We recently found that several CQ-related compounds, including quinacrine (QA) and mefloquine (MQ), have ten-fold greater potency than CQ in killing MPNST cells in vitro. Both QA and MQ have better nervous system penetration than CQ and have been used safely in humans as anti-malarial agents. We have also discovered a number of FDA approved quinolone antibiotics with lysosomotropic properties that show significant tumoricidal activity on MPNST cells in vitro. In this application, we focus on the molecular pathways by which CQ, QA, MQ and other tumoricidal lysosomotropic agents promote MPNST cell death and will critically test the therapeutic potential of these compounds using orthotopic transplantation of MPNST cell lines in nude mice and transgenic mouse models of MPNST tumorigenesis and progression. In aim one, we will test the hypothesis that CQ and other lysosomotropic agents induce MPNST cell death through both apoptotic and autophagic death pathways that are at least in part regulated by altered subcellular distribution and activity of cathepsins, Bax activation of the intrinsic apoptotic death pathway, and disrupted autophagy. Aim two will test the in vivo tumoricidal activity of CQ-related compounds and quinolone antibiotics and their utility as MPNST prophylactic agents in robust mouse models of MPNSTs. In total, these highly integrated studies of MPNSTs will extend our previous investigations of apoptotic and autophagic death pathways, yield new insights into the clinical utility of lysosomotropic therapies for MPNST treatment and prevention, and provide a solid foundation from which to propose future human studies of CQ-related compounds and quinolone antibiotics in NF1 and MPNST patients. PUBLIC HEALTH RELEVANCE: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms that arise in approximately 10% of patients with neurofibromatosis type 1 (NF1) as well as in a significant number of non-NF1 patients. We have found that a variety of lysosomotropic agents such as chloroquine, quinacrine and quinolone antibiotics have significant MPNST killing activity in vitro. This application aims to define their mechanism of tumoricidal action and to test these lysosomotropic compounds in mouse models of MPNSTs.

描述（由申请人提供）：恶性周围神经鞘肿瘤（MPNST）是侵略性的，快速致命的肿瘤，迫切需要新的治疗方法。 MPNST发生在多达10％的神经纤维瘤病患者（NF1）患者中，并且对标准化学治疗剂具有高度耐药性。我们已经研究了近十年的溶酶体氯喹（CQ）（CQ）的细胞死亡活性，发现CQ在多种正常和恶性神经细胞类型中诱导自噬应激和caspase激活。我们假设CQ引起的死亡是由于抑制生存自噬途径以及刺激凋亡和非凋亡死亡途径的刺激。重要的是，CQ诱导的细胞死亡涉及p53依赖性和p53独立途径，并且鉴于人类MPNST在多达75％的病例中显示出p53突变或缺失，因此p53独立的死亡途径可能对有效MPNST治疗特别重要。据报道，CQ是几种癌症动物模型和人类胶质母细胞瘤多形（GBM）患者的标准化学治疗剂的有效佐剂。在这些疾病的转基因小鼠模型中，预防性CQ给药还抑制淋巴瘤形成和动脉粥样硬化疾病。我们最近发现，包括CQ相关的化合物，包括奎诺克林（QA）和甲氟喹（MQ），在体外杀死MPNST细胞方面的效力比CQ高十倍。质量检查和MQ的神经系统渗透都比CQ更好，并且已在人类中被安全地用作抗疟疾剂。我们还发现了许多FDA批准的具有溶酶体特性的奎诺酮抗生素，这些抗生素在体外显示出在MPNST细胞上的显着肿瘤活性。在此应用中，我们专注于CQ，QA，MQ和其他肿瘤性溶酶体剂的分子途径，促进MPNST细胞死亡，并将使用裸小鼠和转基因小鼠模型中MPNST细胞系的原位移植来严格测试这些化合物的治疗潜力MPNST肿瘤发生和进展。在目标中，我们将检验以下假设：CQ和其他溶酶体剂通过凋亡和自噬死亡途径诱导MPNST细胞死亡，至少部分受到cally蛋白的亚细胞分布和活性的调节，Bax激活了内在的凋亡死亡途径。并破坏了自噬。 AIM 2将在强大的MPNST小鼠模型中测试与CQ相关化合物和喹诺酮抗生素的体内肿瘤活性，以及它们作为MPNST预防剂的实用性。总的来说，这些高度综合的MPNST研究将扩展我们先前对凋亡和自噬死亡途径的研究，对MPNST治疗和预防的溶酶体疗法的临床实用性产生新的见解，并提供一个稳固的基础，并提供一个提出未来人类研究的人类研究。 NF1和MPNST患者中与CQ相关的化合物和喹诺酮抗生素。公共卫生相关性：恶性外周神经鞘肿瘤（MPNST）是侵袭性的肿瘤，在大约10％的1型神经纤维瘤病患者（NF1）以及大量非NF1患者中出现。我们发现，各种溶酶体，例如氯喹，喹啉和喹诺酮抗生素在体外具有明显的MPNST杀伤活性。该应用旨在定义其肿瘤作用机制，并在MPNST小鼠模型中测试这些溶酶体化合物。