Stabilizing PID1 to improve medulloblastoma response to cisplatin

稳定 PID1 以改善髓母细胞瘤对顺铂的反应

基本信息

批准号：
9651649
负责人：
ANAT ERDREICH-EPSTEIN
金额：
$ 25.43万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9651649
关键词：
Adipocytes Adverse effects Affect Amino Acids Apoptosis Blood - brain barrier anatomy Bortezomib Brain Brain Neoplasms Cell Line Cells Child Cisplatin Clinical Trials Data Diabetes Mellitus Disease Dose Drug Combinations Future Glioma Growth Half-Life Human Insulin Antagonists Knowledge Lead Link Lysine Malignant Neoplasms Malignant neoplasm of brain Mediating Messenger RNA Mitochondria Molecular Morbidity - disease rate Mus Muscle Cells Mutate Mutation Newly Diagnosed Obesity Paper Pathway interactions Patients Permeability Pharmaceutical Preparations Phase Phase I/II Trial Phosphotyrosine Post-Translational Protein Processing Preclinical Testing Proliferating Proteasome Inhibitor Proteins Proteomics Receptor Signaling Recurrence Regulation Reporting Research Rhabdoid Tumor Role SHH gene Safety Subgroup Testing Therapeutic Toxic effect Transcend Transgenic Mice Translations Tumor Cell Line Ubiquitin Ubiquitination Work base chemotherapy clinically relevant design high risk improved in vivo innovation knock-down medulloblastoma medulloblastoma cell line mimetics mortality mouse model multicatalytic endopeptidase complex mutant novel novel drug combination phase I trial pre-clinical response small molecule tumor tumor growth

项目摘要

Medulloblastoma (MB) is the most common malignant brain tumor in children. We were the first to report on a growth-suppressive effect of PID1 (Phosphotyrosine Interaction Domain containing 1) in MB, constituting the first reported link of PID1 to MB and to cancer overall. We showed that PID1 slowed growth and induced apop- tosis of cell lines from three types of brain tumors, MB, glioma, ATRT, and that lower tumor PID1 mRNA level in MB and glioma tumors correlated with shorter patient survival. Recently we showed that PID1 sensitizes cell lines of MBs and gliomas to chemotherapy, suggesting a potential therapeutic value. Interestingly, PID1 was required for the anti-MB effect of cisplatin, a mainstay of MB chemotherapy. Although cisplatin increased PID1 mRNA, it decreased PID1 protein level in a manner restored by proteasome inhibitors, suggesting that cisplatin promoted proteasomal degradation of PID1. We therefore hypothesize that stabilization of PID1 protein will enhance the anti-MB effect of cisplatin. This hypothesis will be examined in two Specific Aims: 1) To determine PID1 amino acids that are post-translationally modified to mediate cisplatin-dependent deg- radation of PID1 and test if mutating these amino acids to stabilize PID1 will augment the anti-MB effect of cisplatin in culture and in vivo. 2) To determine if proteasome inhibitors augment MB response to cisplatin, if this is via PID1 stabilization, and if the combination is safe and effective against MB in vivo in brains of BarTeL mice. This project will be in cultured MB cells and in our innovative transgenic mouse model for MB, BarTeL and will also test a new brain permeable proteasome inhibitor, marizomib, against intracranial MB in mice. At its con- clusion we will have defined the cisplatin-induced post-translational modifications of PID1, focusing on those that affect protein stability of PID1 and ways to stabilize PID1 in order to enhance efficacy of cisplatin. The potential impact of the knowledge gained is that it will support future translation for patient benefit. In the short term our findings may lead to pre-clinical testing of combination of the new brain-permeable proteasome inhibitor in combination with cisplatin in patients with recurrent MB. In the long term, the knowledge gained will inform our planned design of PID1-based therapeutics to exploit its tumor growth-suppressive effect in MB and other brain tumors.

髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤。我们是第一个报告 MB中PID1的生长抑制作用（含1磷酸酪氨酸相互作用结构域），构成首先报道了PID1与MB和整体癌症的联系。我们表明，PID1降低了生长并诱发了求解来自三种类型的脑肿瘤的细胞系，MB，神经胶质瘤，ATRT和较低的肿瘤PID1 mRNA水平在MB和神经胶质瘤中，肿瘤与较短的患者生存有关。最近，我们表明PID1敏化细胞 MBS和神经胶质瘤的线对化疗，表明潜在的治疗价值。有趣的是，PID1是 Cisplatin的抗MB效应是MB化学疗法的中流stay所必需的。尽管顺铂增加了PID1 mRNA，它以蛋白酶体抑制剂恢复的方式降低了PID1蛋白水平，表明顺铂促进PID1的蛋白酶体降解。因此，我们假设PID1蛋白的稳定将增强顺铂的抗MB作用。该假设将以两个具体的目的进行检查： 1）确定经过翻译后修饰以介导顺铂依赖性DEG-的PID1氨基酸 PID1的辐射并测试是否突变这些氨基酸稳定PID1将增强抗MB的效应培养和体内的顺铂。 2）确定蛋白酶体抑制剂是否增加了MB对顺铂的反应，是否是通过PID1稳定化的如果该组合在Bartel小鼠的大脑中对MB的体内有效且有效。该项目将在培养的MB细胞中以及我们用于MB，Bartel和Will的创新转基因小鼠模型中还可以测试一种新的大脑可渗透性蛋白酶体抑制剂Marizomib，针对小鼠颅内MB。在我们将定义顺铂诱导的PID1翻译后修饰，重点是这会影响PID1的蛋白质稳定性以及稳定PID1的方法以增强顺铂的功效。获得的知识的潜在影响是，它将支持未来的翻译以获得患者的利益。在短期我们的发现可能会导致新的脑渗透蛋白酶体组合的临床前测试复发性MB患者中的抑制剂与顺铂结合。从长远来看，获得的知识将告知我们计划的基于PID1的治疗剂的设计，以利用其在MB和其他脑肿瘤。