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: 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
• 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

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 α2是在几种癌症类型上表达的癌症特异性受体，包括DIPG、胶质母细胞瘤和胶质瘤。 肾上腺皮质癌，并起到绕过由普遍存在的 表达IL 13 R α1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，优先结合IL 13 R α2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 α2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）将IL 13 R α2的RNA和蛋白质表达与基于生物标志物的患者纳入相关联。 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。