Experimental Therapeutics for Brain Cancer

描述（由申请人提供）：脑癌的治疗方法有限，尽管进行了放疗和化疗，但患者的结局往往是死亡。我们已经开发了基于靶向强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都不到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，可以通过颅内输注直接给药到脑肿瘤中。第二，在最常见的脑肿瘤多形性胶质母细胞瘤（GBM）中最常见的细胞表面标记物在一些GBM病例中表达，而在其他病例中则不表达。解决方案是通过结合两种通常对过度表达的GBM标记物起反应的配体来扩大识别肿瘤的范围。这种双特异性抗gbm药物被称为DTAT13。另一个主要问题是，广泛的血管化网络很容易滋养存活的肿瘤细胞，从而导致GBM的复发。我们通过直接针对脉管系统来解决这个问题。我们的药物上的一个配体是针对尿激酶的氨基末端片段（ATF），该片段靶向肿瘤新生血管上过度表达的人尿激酶受体（uPAR）。最后，含有催化毒素的药物有副作用，限制了它们的剂量，我们的数据表明，我们的药物设计降低了它的毒性。迄今为止，所有关于DTAT13的工作都是在小鼠侧腹肿瘤模型上进行的。在第一个目标中，我们将在一个模型中研究我们的药物，这个模型更接近地反映了我们对这些免疫毒素的临床使用，即裸鼠颅内治疗模型。该模型将用于建立工作剂量和剂量表，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性毒性。

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.