Development of Novel Inducers of Non-Apoptotic Cell Death to Target Glioblastoma

开发针对胶质母细胞瘤的新型非凋亡细胞死亡诱导剂

• 批准号: 8372461
• 负责人: WILLIAM A MALTESE
• 金额: $ 28.9万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372461
• 关键词: Adjuvant Therapy; Adult; Affinity; Alkylating Agents; Apoptosis; Apoptotic; Azides; Binding; Binding Proteins; Brain Neoplasms; Caspase; Cell Death; Cell Line; Cells; Cessation of life; Chemicals; Clinical; DNA; DNA Damage; Defect; Development; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Ectopic Expression; Effectiveness; Endocytic Vesicle; Excision; Failure; Gene Mutation; Glioblastoma; Goals; Greek; Homing; Human; Intoxication; Lead; Libraries; Liquid substance; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Membrane; Metabolic; Methamphetamine; Modeling; Molecular Target; Mutation; Names; Nerve Growth Factors; Neurons; Normal Cell; Oligonucleotides; Operative Surgical Procedures; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Primary Brain Neoplasms; Prodrugs; Property; Protein Array Analysis; Proteins; Publishing; Radiation; Radiolabeled; Recurrence; Recycling; Refractory; Reporting; Resistance; Screening procedure; Signal Pathway; Stem cells; Stimulus; Structure; Testing; Therapeutic Agents; Toxic effect; Vacuole; Xenograft Model; Xenograft procedure; acronyms; analog; aptamer; brain cell; cancer cell; cell suicide; crosslink; drinking; improved; innovation; insight; killings; mRNA Differential Displays; medulloblastoma; nanoparticle; neoplastic cell; neuroblastoma cell; novel; novel strategies; nucleolin; outcome forecast; overexpression; prevent; prototype; radiotracer; receptor; response; standard care; temozolomide; therapeutic target; trafficking; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor in adults. Standard treatment involves surgery, followed by radiation and DNA alkylating agents like temozolomide. However, the tumors almost always recur, with median survival remaining in the range of 1-2 years. Current therapies depend on triggering cell suicide (apoptosis) by causing DNA damage, but genetic alterations in GBM cells make them relatively insensitive to apoptotic stimuli. Studies completed during the preceding project period led to the identification of a unique form of cell death termed 'methuosis', which is mechanistically distinct from apoptosis. It involves stimulation of macropinocytosis (cell drinking) together with changes in trafficking of endocytic vesicles, leading to massive cellular vacuolization and loss of membrane integrity. New compounds were discovered to induce methuosis in a broad spectrum of GBM cells, including those that are resistant temozolomide. Structure-activity studies have provided a lead compound referred to by the acronym MOMIPP. The Central Hypothesis underlying the continuation of this project is that a new type of localized therapy for GBM may be realized through the identification of the molecular targets of MOMIPP and the development of nanoparticle (NP) delivery vehicles and/or targeted prodrugs that can be used to direct the compound specifically to GBM. To test this hypothesis three Specific Aims are proposed: Aim-1) Identify the relevant protein target(s) of MOMIPP. This will involve several complementary approaches, including the use of radiolabeled MOMIPP and inactive analogs for differential display analysis of protein arrays, and the use of MOMIPP photoaffinity probes combined with mass spectrometry to identify drug-binding proteins in intact GBM cells. Aim-2) Develop strategies to optimize delivery of MOMIPP to GBM cells. The underlying premise is that MOMIPP might be most effective as an adjuvant therapy for GBM if delivered locally in a sustained release NP formulation. To minimize potential toxicity to normal cells, innovative strategies will be evaluated for selective delivery of the compound to GBM by decorating the NP with GBM-homing peptides or loading them with a MOMIPP prodrug containing a removable GBM-targeting peptide. Aim-3) Evaluate the toxicity, pharmacokinetic properties and anti-tumor efficacy of MOMIPP in GBM xenograft models. Targeted NP and prodrug formulations with the greatest potential for selective delivery of MOMIPP to GBM will be tested in orthotopic xenografts derived from wt and temozolomide-resistant GBM cell lines or stem cells enriched from primary human GBM. These studies are expected to identify formulations that will inhibit tumor progression with minimal systemic toxicity or ill effects on normal neural cells. Impact: The results could have a substantial impact on GBM therapy by validating a new class of drugs that can kill GBM cells by a novel non-apoptotic mechanism. In addition, the development of tumor-homing NP or prodrugs that can be targeted to GBM would represent a technological advance that might be applied more generally for delivery of other therapeutic agents. PUBLIC HEALTH RELEVANCE: Glioblastomas are highly aggressive brain tumors that typically recur after surgery and therapy with radiation and conventional drugs, which kill tumor cells by a classical death pathway termed apoptosis. This project will explore the ability of a new class of chemical compounds to kill glioblastoma cells via a different cell death mechanism and test the effectiveness of innovative tumor-specific drug delivery strategies to avoid collateral damage to normal brain cells. The results could lead to a new approach for treatment of glioblastoma.

描述（由申请人提供）：胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤。标准治疗包括手术，然后是放疗和DNA烷化剂，如替莫唑胺。然而，肿瘤几乎总是复发，中位生存期保持在1-2年的范围内。目前的治疗依赖于通过引起DNA损伤来触发细胞自杀（凋亡），但GBM细胞中的遗传改变使它们对凋亡刺激相对不敏感。在前一个项目期间完成的研究导致了一种独特的细胞死亡形式的鉴定，称为“方法论”，这是机械上不同的 从细胞凋亡。它涉及大胞饮（细胞饮）的刺激以及内吞囊泡运输的变化，导致大量细胞空泡化和膜完整性的丧失。发现新化合物在广谱GBM细胞中诱导甲基化，包括那些耐替莫唑胺的细胞。结构-活性研究提供了首字母缩写为MOMIPP的先导化合物。该项目继续进行的中心假设是，通过鉴定MOMIPP的分子靶标和开发可用于将化合物特异性导向GBM的纳米颗粒（NP）递送载体和/或靶向前药，可以实现GBM的新型局部治疗。为了验证这一假设，提出了三个具体目标：目标-1）鉴定MOMIPP的相关蛋白质靶标。这将涉及几种互补的方法，包括使用放射性标记的MOMIPP和非活性类似物进行蛋白质阵列的差异显示分析，以及使用MOMIPP光亲和探针结合质谱法来鉴定完整GBM细胞中的药物结合蛋白。 目的-2）开发优化MOMIPP向GBM细胞的递送的策略。潜在的前提是，如果以缓释NP制剂局部递送，MOMIPP作为GBM的辅助疗法可能是最有效的。为了最大限度地减少对正常细胞的潜在毒性，将评估通过用GBM归巢肽装饰NP或用含有可去除的GBM靶向肽的MOMIPP前药装载它们来选择性地将化合物递送至GBM的创新策略。目的-3）评价MOMIPP在GBM异种移植模型中的毒性、药代动力学特性和抗肿瘤功效。具有将MOMIPP选择性递送至GBM的最大潜力的靶向NP和前药制剂将在源自wt和替莫唑胺抗性GBM细胞系或富集自原代人GBM的干细胞的原位异种移植物中进行测试。这些研究预计将确定制剂，将抑制肿瘤进展，最小的全身毒性或对正常神经细胞的不良影响。影响：这些结果可能会对GBM治疗产生重大影响，通过验证一类新的药物，可以通过一种新的非凋亡机制杀死GBM细胞。此外，可以靶向GBM的肿瘤归巢NP或前药的开发将代表可能更普遍地应用于递送其他治疗剂的技术进步。 公共卫生关系：胶质母细胞瘤是一种高度侵袭性的脑肿瘤，通常在手术和放射治疗以及常规药物治疗后复发，这些药物通过称为细胞凋亡的经典死亡途径杀死肿瘤细胞。该项目将探索一种新的 这类化合物通过不同的细胞死亡机制杀死胶质母细胞瘤细胞，并测试创新的肿瘤特异性药物递送策略的有效性，以避免对正常脑细胞的附带损伤。这一结果可能为胶质母细胞瘤的治疗提供一种新的方法。