Experimental Therapeutics for Brain Cancer

脑癌的实验治疗

• 批准号: 7054130
• 负责人: Daniel A Vallera
• 金额: $ 23.07万
• 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/7054130
• 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（由申请人提供）：脑癌治疗的替代方案有限，尽管进行了放射和化疗治疗，患者的结果通常是死亡。我们开发了基于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。首先，任何重组生物制剂的注射剂量只有不到 0.001% 到达肿瘤，因此我们正在研究一种通过基因工程融合蛋白的解决方案，该解决方案可以通过颅内输注直接注射到脑肿瘤中。其次，多形性胶质母细胞瘤 (GBM)（最常见的脑肿瘤形式）中最常见的细胞表面标志物在某些 GBM 病例中表达，但在其他病例中不表达。解决方案是通过合并两种通常与过度表达的 GBM 标记物发生反应的配体来扩大识别的肿瘤范围。这种双特异性抗 GBM 药物被称为 DTAT13。另一个主要问题是广泛的血管网络很容易滋养存活的肿瘤细胞，从而导致 GBM 复发。我们通过直接针对脉管系统来解决这个问题。我们的药物上的配体之一针对尿激酶的氨基末端片段（ATF），该片段以肿瘤新血管系统上过度表达的人尿激酶受体（uPAR）为目标。最后，含有催化毒素的药剂具有限制其剂量的副作用，并且我们的数据表明我们的药剂的设计降低了其毒性。迄今为止，所有关于 DTAT13 的工作都是在小鼠胁腹肿瘤模型上进行的。在目标一中，我们将在更接近地反映我们对这些免疫毒素的临床使用的模型中研究我们的药物，即颅内治疗的裸啮齿动物模型。该模型将用于建立工作剂量和剂量计划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代动力学、在非靶器官中的分布，并在更接近其在人类中的使用的模型中研究剂量限制毒性。