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

GB13 的开发用于治疗儿童弥漫性内源性脑桥胶质瘤

• 批准号: 10739601
• 负责人: Randy Schrecengost
• 金额: $ 5.5万
• 依托单位: TARGEPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10739601
• 关键词: Adrenocortical carcinoma; Binding; Biological Markers; Biopsy; Blood - brain barrier anatomy; Brain Stem; Bypass; Cells; Child; Childhood; Childhood Glioma; Clinical; Clinical Trials; Convection; Data; Detection; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disease; Drug Delivery Systems; Exotoxins; Genetic Transcription; Glioblastoma; Glioma; Induction of Apoptosis; Interleukin-13; Intervention; Location; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Methods; Molecular; Mutate; Pathway interactions; Patients; Pediatric Neoplasm; Play; Pontine structure; Pseudomonas aeruginosa toxA protein; Radiation; Radiation therapy; Radiosensitization; Therapeutic; Toxin; Treatment Efficacy; Work; brain tissue; cancer cell; cancer type; clinical development; disease prognosis; effective therapy; improved; in vivo; inclusion criteria; mouse model; neoplastic cell; new therapeutic target; palliation; phase I trial; protein expression; radiation response; receptor; response; treatment response; tumor

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. IL13R2 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 IL13R1 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 IL13R2 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 IL13R2-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 IL13R2 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.

项目总结/摘要 弥漫性内在脑桥胶质瘤是一种罕见的，儿科肿瘤，通常发生在腹侧的脑桥， 脑干没有有效的治疗方案。美国每年大约有400名儿童被诊断出 与这种疾病。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发挥了关键作用。目前唯一的治疗方法是放射治疗 然而，在这种治疗中，肿瘤反应非常少，并且这种干预主要限于减轻。新 改善放射反应的治疗选择将显著提高这种治疗的持久性。 克服由血脑屏障产生的药物递送挑战的一种机制是通过 对流增强输送（CED），可将治疗直接施用于肿瘤， 功效因此，该提案将新型靶向治疗与CED相结合，以显着推进治疗 DIPG患者的反应。 IL 13 R β 2是在几种癌症类型上表达的癌症特异性受体，包括DIPG、胶质母细胞瘤和成胶质细胞瘤。 肾上腺皮质癌，并起到绕过由普遍存在的 表达IL 13 R β 1和IL 13。肿瘤细胞的限制也提供了一个机会， 癌细胞通过利用IL 13/受体协会。因此，Targepeutics开发了一种突变的IL 13- 衍生毒素，称为GB 13，其优先结合IL 13 R β 2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工作，以开发GB 13的临床进展， 1）测定GB 13对IL 13 R β 2阳性小鼠模型的体内功效， 2）分析GB 13增加DIPG细胞对DIPG的敏感性的能力， 辐射，和3）关联IL 13 R β 2的RNA和蛋白质表达，用于基于生物标记物的患者纳入。 本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。

项目成果

IL-13Rα2 Status Predicts GB-13 (IL13.E13K-PE4E) Efficacy in High-Grade Glioma.

• DOI: 10.3390/pharmaceutics14050922
• 发表时间: 2022-04-24
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Rechberger, Julian S.;Porath, Kendra A.;Zhang, Liang;Nesvick, Cody L.;Schrecengost, Randy S.;Sarkaria, Jann N.;Daniels, David J.
• 通讯作者: Daniels, David J.