GSK3 inhibition as an adjuvant therapy for Burkitt's lymphoma

GSK3 抑制作为伯基特淋巴瘤的辅助治疗

基本信息

批准号：
8788701
负责人：
Andrei Thomas-Tikhonenko
金额：
$ 25.58万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788701
关键词：
Acute Adjuvant Adjuvant Therapy Affect Antisense RNA Apoptosis Apoptotic B-Cell Lymphomas B-Lymphocytes Blood Bone Marrow Bortezomib Burkitt Lymphoma Cell Death Cell Line Cell Proliferation Cells Cessation of life Chemosensitization Chronic Data Disease-Free Survival Doxorubicin Event Experimental Designs FDA approved Feedback Genetic Genets Glycogen Synthase Kinase 3 Goals Health Homeostasis Human In Vitro Knock-in Mouse Life Lithium Lithium Chloride Lymphoma Lymphomagenesis MDM2 gene Malignant Neoplasms Mental disorders Methods MicroRNAs Modeling Mus Mutate Noxae Oncogene Proteins Oncogenes PMAIP1 gene Pathway interactions Patients Pharmaceutical Preparations Phase I/II Trial Preparation Reagent Regimen Regulation Research Retroviridae System Tamoxifen Testing Therapeutic Time Up-Regulation Work Xenograft procedure base c-myc Genes c-myc Proto-Oncogenes cancer therapy chemotherapy in vivo inhibitor/antagonist innovation large cell Diffuse non-Hodgkin&apos s lymphoma mutant novel protein degradation research study response rituximab standard of care tumor

项目摘要

DESCRIPTION (provided by applicant): The c-Myc proto-oncogene is a key factor in both B-cell homeostasis and B-lymphomagenesis. Its transforming potential is based largely on its ability to drive cell proliferation. At the same time, Myc can also induce apoptosis, either throug induction of p53 or in a p53-independent manner. Yet the goal of channeling the pro-apoptotic activity of Myc toward anti-cancer therapies has so far proven elusive, primarily because methods to transiently increased Myc levels didn't exist. Our recent research showed that boosting Myc expression elevates p53 and increases sensitivity to bortezomib. One limitation of that study was the reliance on the p53 pathway, which is frequently lost in human B-lymphomas. To determine how Myc contributes to p53-independent apoptosis in a bona fide therapeutic setting (CHOP therapy), we now used cells isolated from bone marrows of p53ERTAM knock-in mice and subsequently transduced with a Myc-expressing retrovirus. This inducible system allowed us to distinguish between p53-dependent (cells treated with tamoxifen) and independent (no tamoxifen given) cell deaths. Additionally, very recent data from our lab show that GSK-3¿ is actively involved in the regulation of Myc protein degradation in B-cells, and that inhibition of GSK-3¿ with CHIR99021 sharply increases Myc levels. Using these reagents, we observed that pharmacological stabilization of Myc with GSK-3¿ inhibitors strongly enhanced p53-independent doxorubicin-induced apoptosis. Most importantly, even in p53-mutated Ramos Burkitt's lymphoma cells, Myc stabilization resulted in increased responses to doxorubicin. These results fully support our innovative hypothesis that transient up-regulation of Myc could be a viable adjuvant therapy for Myc-driven tumors even with p53 loss or MDM2 amplification. We will pursue this hypothesis in the following two aims. 1) To investigate Myc-dependent and - independent events that drive p53-independent apoptosis in response to doxorubicin+GSK3¿ inhibitors. Specifically, we will determine whether genetic or pharmacological inhibition of Myc abolishes pro- apoptotic effects of CHIR99021 or whether other GSK-3¿ targets such as BCL2L12 contribute to chemosensitization. 2) To investigate how GSK3¿ inhibition affects Burkitt's lymphoma response to doxorubicin in acute and chronic treatment models. On the strength of our in vitro data, we will test if GSK-3¿ inhibition potentiates doxorubicin-based chemotherapy against murine syngeneic grafts and human xenografts, resulting in a more robust apoptotic response (acute model) and prolonged event- free survival (chronic model). Upon completion of this work we will have a better understanding of the apoptotic pathways regulated by GSK3¿ and its targets such as Myc and BCL2L12. Also, we will validate GSK3¿ inhibitors as adjuvant therapeutics to treat Myc-driven B cell lymphomas with mutant p53 or MDM2 amplification.

描述（由申请人提供）：C-Myc原始癌基因是Bot稳态和B淋巴结的关键因素。到目前为止，p53的抗癌疗法已经证明是难以捉摸的。在人类B淋巴瘤中经常丢失，以确定Myc如何在真正转导Myc表达逆转录病毒的p53-独立的凋亡。另外，来自我们实验室的最新数据还表明，GSK-3¿3¿在B细胞中MYC蛋白降解的调节中进行了激活，并继承GSK-3？随着CHIR99021的使用，使用这些试剂急剧提高了MYC的水平，我们观察到MYC与GSK-3？3€的药理学稳定性抑制剂强烈增强了p53依赖性的doxorubed凋亡 - 依赖性和独立的事件，响应阿霉素+gsk3挥之不去的事件抑制剂。诸如Bcl2L12之类的靶标有助于化学敏感。抑制伯基特对急性和慢性治疗模型中阿霉素的淋巴瘤反应。抑制作用基于阿霉素的化学疗法对鼠的合成性移植物和人异种移植物，从而导致更健壮的凋亡反应（急性模型）和延长的事件 - 自由生存（慢性模型）。由GSK3的途径及其目标，例如MYC和BCL2L12。抑制剂作为辅助治疗剂，可信任通过突变p53或MDM2扩增的MYC驱动的B细胞淋巴瘤。