Molecular Combinatorial Therapy of Glioblastoma Multiforme

多形性胶质母细胞瘤的分子组合治疗

• 批准号: 8010645
• 负责人: Waldemar Debinski
• 金额: $ 30.92万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010645
• 关键词: Address; Animals; Antineoplastic Agents; Bacterial Toxins; Binding Sites; Brain; Brain Neoplasms; Breeding; CRM 107; Canis familiaris; Cell Line; Cell membrane; Cells; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Convection; Cytotoxin; Data; Diphtheria Toxin; Drug Delivery Systems; EphA2 Receptor; Exhibits; Gadolinium; Generations; Glioblastoma; Human; Image; Imaging Techniques; In Vitro; Interleukin-13; Label; Laboratory Research; Ligands; Light; Link; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Medicine; Membrane Proteins; Modeling; Molecular; Molecular Profiling; Molecular Target; Monitor; Neuraxis; Outcome; PET/CT scan; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase III Clinical Trials; Play; Positron-Emission Tomography; Pre-Clinical Model; Prevalence; Progression-Free Survivals; Pseudomonas aeruginosa toxA protein; Receptor Protein-Tyrosine Kinases; Recombinants; Recurrence; Relative (related person); Reporting; Rodent Model; Role; Safety; Serum Albumin; Site; Solutions; Specificity; Specimen; System; Testing; Therapeutic Intervention; Tracer; Work; base; cell killing; clinical application; clinical efficacy; combinatorial; drug candidate; drug distribution; follow-up; fos-related antigen 1; gadolinium oxide; human disease; in vivo Model; neoplastic cell; neovasculature; novel; patient population; prototype; public health relevance; receptor; standard of care; tool; tumor

DESCRIPTION (provided by applicant): There has been a substantial progress in clinical application of molecularly targeted proteinaceous cytotoxins for the treatment of glioblastoma multiforme (GBM). Several cytotoxins have moved relatively quickly, as for novel anti-cancer drugs, from bench to clinic and these studies brought invaluable translational information. Based on clinical trials and laboratory research, we hypothesize that there are three important factors linked to the overall cytotoxins' clinical utility. One is the target specificity. Another factor impacting efficacy of cytotoxins is the relative percentage of patients' population that can be predicted to be the responders to a cytotoxin. And the third factor, an efficient delivery of the cytotoxin directly to the tumor site using convection-enhanced delivery (CED) has been proven to be effective in many cases, but it is ordinarily not monitored. These hypotheses will be tackled experimentally, since we have all the tools needed to do so. With regard to target specificity, it was found that a vast majority of GBM patients over-express binding sites for interleukin 13 (IL-13), IL-13Ra2. Furthermore, another receptor, EphA2 tyrosine kinase receptor, was found to be elevated in a large number of GBM specimens and cell lines, but not in normal brain. A prototype cytotoxin targeting EphA2 has been successfully generated. With regard to the population of patients being potential responders to the cytotoxins, over-expression of IL-13Ra2 and Epha2 together is present in almost 100% of patients with GBM and thus it is an ideal situation in which all patients could be predictably responders or eligible for treatment. With regard to recombinant cytotoxins' delivery to GBM, it was demonstrated that using gadolinium and labeled human serum albumin (HSA) a faithful monitoring of drug distribution through CED can be obtained. In addition, some breeds of dogs express molecular fingerprints similarly to human GBM and represent an attractive, large animal pre-clinical model of human disease; the CED has already been applied to the central nervous system of dogs. Therefore, three Specific Aims are proposed. Specific Aim #1 is to optimize a novel molecularly targeted anti-GBM agent that exploits specific over-expression of EphA2 receptor in GBM. We will continue the work on an ephrinA1-based bacterial toxin-containing cytotoxin that exhibit potent and specific GBM cell killing. Specific Aim #2 is to explore combinatorial targeting of EphA2 and IL- 13Ra2 receptors with the cytotoxins. The combination therapy will be tested for an anti-tumor efficacy in in vitro and in vivo models of human GBM. In Specific Aim #3, Phase I clinical trial in dogs with malignant gliomas using combinatorial recombinant cytotoxins approach will be performed. The distribution of the CED- delivered drugs will be monitored long- and short-term by employing MRI and PET and using Gd-HSA and [68]Ga-HSA, respectively. The results of this project will permit further successful clinical application of recombinant cytotoxins, a highly promising class of anti-GBM drugs. PUBLIC HEALTH RELEVANCE: Most malignant tumors of the brain, including glioblastoma multiforme (GBM) remain incurable and thus represent unmet need in medicine. We have found a way to target specifically tumor cells with potent tumor cell killing agents in combination that would be applicable to almost all patients with GBM. We are also working on a controlled way to deliver these agents to brain tumors. It is expected that this approach will have impact on the overall survival of patients with GBM.

描述（由申请人提供）：分子靶向蛋白质细胞毒素治疗多形性胶质母细胞瘤（GBM）的临床应用已取得实质性进展。一些细胞毒素已经相对快速地从实验室进入临床，这些研究带来了宝贵的翻译信息。基于临床试验和实验室研究，我们假设有三个重要因素与总体细胞毒素的临床效用相关。一是目标特异性。影响细胞毒素功效的另一个因素是可预测为细胞毒素应答者的患者群体的相对百分比。第三个因素，使用对流增强递送（CED）将细胞毒素直接有效递送到肿瘤部位已被证明在许多情况下是有效的，但通常不进行监测。这些假设将通过实验来解决，因为我们拥有这样做所需的所有工具。关于靶特异性，发现绝大多数GBM患者过表达白细胞介素13（IL-13）、IL-13 Ra 2的结合位点。此外，另一种受体，EphA 2酪氨酸激酶受体，被发现在大量的GBM标本和细胞系中升高，但在正常脑中不升高。已经成功地产生了靶向EphA 2的原型细胞毒素。关于作为细胞毒素的潜在应答者的患者群体，IL-13 Ra 2和Epha 2一起的过表达存在于几乎100%的GBM患者中，因此这是一种理想的情况，其中所有患者都可以是可预测的应答者或适合治疗。关于重组细胞毒素向GBM的递送，证明了使用钆和标记的人血清白蛋白（HSA）可以通过CED获得药物分布的忠实监测。此外，一些品种的狗表达类似于人类GBM的分子指纹，代表了一种有吸引力的大型动物人类疾病临床前模型; CED已经应用于狗的中枢神经系统。因此，提出了三个具体目标。具体目标#1是优化利用EphA 2受体在GBM中的特异性过表达的新型分子靶向抗GBM剂。我们将继续研究一种基于ephrinA 1的含有细菌毒素的细胞毒素，该毒素具有强效和特异性的GBM细胞杀伤作用。具体目标#2是探索EphA 2和IL-13 Ra 2受体与细胞毒素的组合靶向。将在人GBM的体外和体内模型中测试组合疗法的抗肿瘤功效。在具体目标#3中，将使用组合重组细胞毒素方法在患有恶性胶质瘤的犬中进行I期临床试验。CED递送药物的分布将分别通过采用MRI和PET以及使用Gd-HSA和[68]Ga-HSA进行长期和短期监测。该项目的结果将允许重组细胞毒素的进一步成功临床应用，这是一类非常有前途的抗GBM药物。 公共卫生关系：大多数脑部恶性肿瘤，包括多形性胶质母细胞瘤（GBM）仍然无法治愈，因此代表了医学上未满足的需求。我们已经找到了一种方法，可以将有效的肿瘤细胞杀伤剂与肿瘤细胞特异性靶向结合，这将适用于几乎所有GBM患者。我们还在研究一种可控的方法来将这些药物输送到脑肿瘤中。预计这种方法将对GBM患者的总生存期产生影响。