Experimental Therapeutics for Brain Cancer

脑癌的实验治疗

• 批准号: 6917349
• 负责人: Daniel A Vallera
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917349
• 关键词: Macaca mulatta; athymic mouse; autoradiography; blood brain barrier; brain imaging /visualization /scanning; brain neoplasms; cerebral hemorrhage; cerebrovascular occlusions; disease /disorder model; drug delivery systems; drug screening /evaluation; glioblastoma multiforme; histopathology; immunoconjugates; interleukin 13; magnetic resonance imaging; neoplasm /cancer blood supply; neoplasm /cancer immunotherapy; neurotoxicology; nonhuman therapy evaluation; perfusion; pharmacokinetics; urokinase

DESCRIPTION (provided by applicant): Alternatives are limited for therapy of brain cancer and the patient outcome, despite radiation and chemotherapy treatment, is often death. We have developed recombinant biological agents based on targeting potent catalytic toxins that can address some of the major problems in the field. The first is that less than 0.001 % of the injected dose of any recombinant biological agent ever reaches the tumor and so we are investigating a solution by genetically engineering fusion proteins that can be administered directly into brain tumors using intracranial infusion. The second is that cell surface markers that are most commonly targeted in glioblastoma multiform (GBM), the most common form of brain tumor, are expressed on some GBM cases, but not on others. The solution was to broaden the range of tumors recognized by incorporating two ligands that commonly react against overexpressed GBM markers. This bispecific anti-GBM agent was called DTAT13. Another major problem is that an extensive network of vascularization readily nourishes surviving tumor cells contributing to GBM reoccurrence. We addressed this by directly targeting the vasculature. One of the ligands on our agent was directed against the amino terminal fragment (ATF) of urokinase that targets the human urokinase receptor (uPAR) overexpressed on tumor neovasculature. Finally, agents incorporating catalytic toxins have side effects that limit their dosage and our data indicate that the design of our agent reduces its toxicity. All of the work on DTAT13 to date has been performed on a mouse flank tumor model. In aim one, we will study our agent in a model that more closely mirrors our clinical use of these immunotoxins, i.e., a nude rodent model of intracranial therapy. The model will be used to establish working doses and dose schedules and address the critical issue of tumor reoccurrence. In the second aim, we will use primates to determine the pharmacokinetics, distribution into non-target organs, and to study the dose limiting toxicities in a model that more closely approximates its use in humans.

描述(申请人提供)：脑癌的治疗选择有限，尽管接受了放射和化疗，但患者的结局往往是死亡。我们已经开发了基于靶向有效催化毒素的重组生物制剂，可以解决该领域的一些主要问题。第一，只有不到0.001%的注射剂量的重组生物制剂到达肿瘤，所以我们正在研究一种解决方案，通过基因工程融合蛋白，可以通过颅内输注直接注射到脑瘤中。第二，在最常见的脑肿瘤形式--多形性胶质母细胞瘤(GBM)中，最常见的靶向细胞表面标志在一些GBM病例上表达，但在其他病例上不表达。解决方案是通过结合两种通常对过度表达的GBM标记起反应的配体来扩大肿瘤识别的范围。这种双特异性抗GBM试剂被称为DTAT13。另一个主要问题是，广泛的血管形成网络很容易滋养存活的肿瘤细胞，导致基底膜复发。我们通过直接针对血管系统来解决这个问题。我们试剂上的一个配体针对的是尿激酶的氨基末端片段(ATF)，它针对的是肿瘤新生血管上过表达的人尿激酶受体(UPAR)。最后，含有催化毒素的试剂有副作用，限制了它们的剂量，我们的数据表明，我们的试剂的设计降低了它的毒性。到目前为止，所有关于DTAT13的工作都是在小鼠侧翼肿瘤模型上进行的。在第一个目标中，我们将在一个更接近于我们临床使用这些免疫毒素的模型中研究我们的试剂，即，颅内治疗的裸鼠模型。该模型将用于建立工作剂量和剂量时间表，并解决肿瘤复发的关键问题。在第二个目标中，我们将使用灵长类动物来确定药物动力学，在非靶器官中的分布，并在一个更接近于人类使用的模型中研究剂量限制毒性。