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（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。就新型抗癌药物而言，几种细胞毒素从实验室转移到临床的速度相对较快，这些研究带来了宝贵的转化信息。根据临床试验和实验室研究，我们假设三个重要因素与细胞毒素的整体临床效用相关。一是目标特异性。影响细胞毒素功效的另一个因素是可以预测对细胞毒素有反应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至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。关于靶标特异性，发现绝大多数 GBM 患者过度表达白细胞介素 13 (IL-13)、IL-13Ra2 的结合位点。此外，另一种受体，EphA2酪氨酸激酶受体，被发现在大量GBM样本和细胞系中升高，但在正常大脑中却没有升高。已成功生成针对 EphA2 的原型细胞毒素。关于对细胞毒素有潜在反应者的患者群体，几乎 100% 的 GBM 患者中都存在 IL-13Ra2 和 Epha2 的过度表达，因此这是一种理想的情况，其中所有患者都可以成为可预测的反应者或有资格接受治疗。关于重组细胞毒素向 GBM 的递送，已证明使用钆和标记的人血清白蛋白 (HSA) 可以通过 CED 准确监测药物分布。此外，某些品种的狗表达与人类 GBM 类似的分子指纹，代表了人类疾病的一种有吸引力的大型动物临床前模型； CED 已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是优化一种新型分子靶向抗GBM药物，该药物利用GBM中EphA2受体的特异性过度表达。我们将继续研究基于 ephrinA1 的含有细胞毒素的细菌毒素，该毒素具有有效且特异性的 GBM 细胞杀伤作用。具体目标#2是探索EphA2和IL-13Ra2受体与细胞毒素的组合靶向。该联合疗法将在人类 GBM 的体外和体内模型中测试其抗肿瘤功效。在具体目标#3中，将使用组合重组细胞毒素方法对患有恶性神经胶质瘤的狗进行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。该项目的结果将使重组细胞毒素（一类非常有前途的抗GBM药物）在临床上得到进一步成功的应用。 公共卫生相关性：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，因此代表了未满足的医学需求。我们已经找到了一种联合有效的肿瘤细胞杀伤剂特异性靶向肿瘤细胞的方法，该方法适用于几乎所有 GBM 患者。我们还在研究一种受控方法将这些药物递送至脑肿瘤。预计这种方法将对 GBM 患者的总体生存产生影响。