Development of GB13 for the Treatment of Pediatric Diffuse Intrinsic Pontine Glioma

项目摘要/摘要 弥漫性桥脑胶质瘤(DIPG)是一种罕见的儿科肿瘤，通常发生在脑桥腹侧。 脑干没有有效的治疗选择。美国每年约有400名儿童被诊断出 得了这种病。DIPG的物理位置、血脑屏障和有限的分子理解 在无法改善疾病预后方面起了关键作用。目前，唯一的治疗选择是放射治疗。 然而，治疗对肿瘤的反应很小，这种干预主要局限于姑息治疗。新的 改善辐射反应的治疗方案将显著提高这种治疗的持久性。 克服血脑屏障造成的药物输送挑战的一种机制是通过 对流增强输送(CED)，直接对肿瘤进行治疗并增加治疗 功效。因此，这项建议将一种新的靶向治疗与CED相结合，以显著推进治疗 对DIPG患者的反应。 IL13Rα2是一种肿瘤特异性受体，表达于多种癌症类型，包括DIPG、胶质母细胞瘤和 肾上腺皮质癌及其绕过无处不在的细胞凋亡诱导途径的功能 表达IL-13Rα-1和IL-13。肿瘤细胞的限制也提供了一种特定靶向的机会 肿瘤细胞通过利用IL13/受体的联合作用。因此，Targepeutics已经开发出一种突变的IL13- 衍生毒素，称为GB13，优先与IL13Rα2结合，并具有假单胞菌外毒素部分 杀死目标细胞。 该项目的三个目标独立地致力于开发GB13在临床上的进展 银杏叶提取物对IL-13Rα-2阳性小鼠模型的体内治疗作用 通过CED给予DIPG，2)分析GB13增加DIPG细胞对 辐射，以及3)IL13Rα2RNA和蛋白表达与基于生物标记物的患者纳入的相关性。 该提案的预期结果将提供必要的概念验证数据，以支持IND 提交第一阶段试验。

PROJECT SUMMARY/ABSTRACT Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, pediatric tumor typically arising in the ventral pons of the brainstem with no effective treatment options. Every year approximately 400 children in the US are diagnosed with this disease. Physical location, the blood-brain barrier and limited molecular understanding of DIPG have played key roles in the inability to improve disease prognosis. Currently, the only treatment option is radiation therapy, however, there is very little tumor response and this intervention is limited primarily to palliation. New treatment options that improve the radiation response will significantly advance this therapeutic durability. One mechanism to overcome drug delivery challenges created by the blood-brain barrier is through convection enhanced delivery (CED), which administers treatments directly into tumors and increases treatment efficacy. As such, this proposal combines a novel targeted therapy with CED to dramatically advance treatment response for DIPG patients. IL13Rα2 is a cancer-specific receptor expressed on several cancer types, including DIPG, glioblastoma and adrenal cortical carcinoma, and functions to bypass the apoptosis-inducing pathway mediated by ubiquitously expressed IL13Rα1 and IL13. The tumor cell restriction also provides an opportunity to specifically target cancer cells by leveraging IL13/receptor association. As such, Targepeutics has developed a mutated IL13- derived toxin, called GB13, that preferentially binds to IL13Rα2 and possesses a Pseudomonas exotoxin moiety to kill targeted cells. The three aims of this project independently work to develop the clinical advancement of GB13 for the treatment of DIPG by; 1) determining the in vivo efficacy of GB13 for IL13Rα2-positive mouse models of DIPG when administered via CED, 2) analyzing the ability of GB13 to increase sensitivity of DIPG cells to radiation, and 3) correlating RNA and protein expression of IL13Rα2 for biomarker-based patient inclusion. The expected results of this proposal will provide necessary proof-of-concept data to support an IND submission for a phase I trial.