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

基本信息

批准号：
10547899
负责人：
Randy Schrecengost
金额：
$ 27.5万
依托单位：
TARGEPEUTICS, INC.
依托单位国家：
美国
项目类别：
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/10547899
关键词：
Adrenocortical carcinoma Affect Affinity Age Anatomy Animals Apoptosis Binding Biological Markers Biological Response Modifier Therapy Biopsy Biopsy Specimen Blood - brain barrier anatomy Brain Neoplasms Brain Stem Businesses Bypass Caspase Cell Death Cell Surface Receptors Cells Cessation of life Child Childhood Childhood Brain Neoplasm Childhood Glioma Childhood Malignant Brain Tumor Clinic Clinical Clinical Trials Convection Cytotoxin Data Detection Development Diagnosis Diffuse intrinsic pontine glioma Disease Disease Outcome Disease Progression Drug Delivery Systems Drug Utilization Effectiveness Endotoxins Engineering Epigenetic Process Exotoxins Future Genetic Engineering Genetic Transcription Glioblastoma Glioma Histone H3 Human Immune Immunotoxins Implant In Vitro Interleukin-13 Intervention Location Malignant Childhood Neoplasm Malignant Glioma Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of ovary Measures Mediating Methods Methylation Modification Molecular Molecular Profiling Multi-site clinical study Mutate Mutation Normal Cell Orphan Drugs Palliative Care Pathway interactions Patients Pediatric Neoplasm Phase Phase I Clinical Trials Play Pontine structure Proteins Pseudomonas aeruginosa toxA protein RNA Radiation Radiation therapy Radiosensitization Resistance Sampling Signal Transduction Surface Testing Therapeutic Therapeutic Index Toxic effect Toxin Treatment Efficacy United States Work base biobank brain cell brain tissue cancer cell cancer type clinical development clinical practice clinically relevant cytokine cytotoxic diffuse midline glioma disease prognosis effective therapy improved in vivo in vivo Model inclusion criteria interleukin-13 receptor melanoma mouse model mutant neoplastic cell new therapeutic target palliation phase I trial pre-clinical preclinical efficacy preclinical trial protein expression radiation response receptor receptor function response selective expression standard of care targeted treatment transcriptome sequencing treatment response tumor tumor progression

项目摘要

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.

项目摘要/摘要弥漫性内在的庞然神经胶质瘤（DIPG）是一种罕见的小儿肿瘤，通常在该腹侧出现脑干没有有效的治疗选择。每年在美国大约有400名儿童被诊断出有这种疾病。物理位置，血脑屏障和对DIPG的分子理解有限的在无法改善疾病进展方面发挥了关键作用。目前，唯一的治疗选择是辐射然而，治疗几乎没有肿瘤反应，这种干预措施主要限于抑制。新的改善辐射反应的治疗方案将显着提高这种治疗耐用性。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的分娩（CED），该递送直接将治疗直接用于肿瘤并增加治疗功效。因此，该提案结合了一种新型的靶向疗法和CED，以极大地提高治疗 DIPG患者的反应。 IL13Rα2是一种癌症特异性受体，在几种癌症类型上表达，包括DIPG，胶质母细胞瘤和肾上腺皮质癌，以及绕过凋亡诱导的途径的功能表达IL13Rα1和IL13。肿瘤细胞限制还提供了一个专门针对的机会通过利用IL13/受体关联来癌细胞。因此，Targepeutics开发了突变的IL13- 衍生的毒素，称为GB13，优先结合IL13Rα2并具有假单胞菌Exotoxin部分杀死目标细胞。该项目的三个目标独立努力开发GB13的临床进步 dipg的处理； 1）确定GB13的体内效率对于IL13Rα2阳性小鼠模型的体内效率 DIPG通过CED给药，2）分析GB13提高DIPG细胞敏感性的能力辐射和3）将基于生物标志物的患者包容性IL13Rα2的RNA和蛋白质表达相关。该提案的预期结果将提供必要的概念证明数据以支持IND 提交I期审判。