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）是儿童中最常见的恶性脑肿瘤。我们是第一个报道 MB 中 PID1（包含 1 的磷酸酪氨酸相互作用域）的生长抑制作用，构成首次报道了 PID1 与 MB 以及总体癌症的联系。我们发现 PID1 减缓生长并诱导细胞凋亡来自三种类型脑肿瘤（MB、神经胶质瘤、ATRT）的细胞系的分裂，并降低肿瘤 PID1 mRNA 水平 MB 和神经胶质瘤肿瘤与较短的患者生存期相关。最近我们发现 PID1 使细胞敏感 MB 和神经胶质瘤与化疗的关系，表明潜在的治疗价值。有趣的是，PID1 是顺铂（MB 化疗的主要成分）的抗 MB 作用所需。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 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。该假设将在两个具体目标中进行检验： 1) 确定经过翻译后修饰以介导顺铂依赖度的 PID1 氨基酸 PID1 的辐射并测试突变这些氨基酸以稳定 PID1 是否会增强培养物和体内的顺铂。 2) 为了确定蛋白酶体抑制剂是否增强 MB 对顺铂的反应，如果这是通过 PID1 稳定，以及该组合是否安全有效地对抗 BarTeL 小鼠大脑中的体内 MB。该项目将在培养的 MB 细胞和我们创新的 MB、BarTeL 转基因小鼠模型中进行，并将还测试了一种新的脑渗透性蛋白酶体抑制剂 Marizomib 对抗小鼠颅内 MB 的作用。在其con- 综上所述，我们将定义顺铂诱导的 PID1 翻译后修饰，重点关注那些影响PID1蛋白稳定性的因素以及稳定PID1以增强顺铂疗效的方法。所获得的知识的潜在影响是，它将支持未来的转化，以造福于患者。在短期内，我们的发现可能会导致新的脑渗透性蛋白酶体组合的临床前测试抑制剂与顺铂联合治疗复发性 MB 患者。从长远来看，所获得的知识将告知我们基于 PID1 的疗法的计划设计，以利用其在 MB 和中的肿瘤生长抑制作用其他脑肿瘤。