Modulating Glioblastoma Stem Cell Clonal Evolution Towards Therapeutic Responsiveness

调节胶质母细胞瘤干细胞克隆进化以实现治疗反应

基本信息

批准号：
10226332
负责人：
Arnold Etame
金额：
$ 20.59万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226332
关键词：
Affect Apoptosis Apoptotic BIRC3 gene Back Binding Biological Assay Biological Markers Brain Neoplasms Cell Line Cell Nucleus Cell model Cells Clonal Evolution Development Disease Environment Failure Foundations Gene Expression Genes Genetic Transcription Glioblastoma Glioma Goals HIF1A gene Heterodimerization Hypoxia Knowledge Lead Malignant - descriptor Malignant Neoplasms Mediating Mediator of activation protein Mesenchymal Molecular Mutation N-terminal Neurosurgeon Nuclear Translocation Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Phenotype Phosphorylation Positioning Attribute Prognosis Publishing Radiation therapy Recurrence Research Priority Resistance Resources Role STAT3 gene Signal Transduction Therapeutic Tissues Translating Treatment Failure Up-Regulation Xenograft procedure aggressive therapy clinical practice design drug discovery genetic signature immunotherapy trials improved in vivo inhibitor-of-apoptosis protein innovation molecular subtypes novel novel strategies patient derived xenograft model prevent programs response stem cells survival outcome temozolomide therapy development therapy resistant transcription factor transcriptome sequencing treatment strategy tumor tumor growth ubiquitin-protein ligase

项目摘要

Glioblastoma (GBM) is a uniformly lethal cancer with a dismal median survival following surgery, Temozolomide (TMZ) and Radiotherapy (RT). Futile attempts with second-line therapies for GBM as well as recent failures in GBM immunotherapy trials further underscore the strong need for new paradigms in GBM. One hypothesis of treatment resistance in GBMs is that Brain Tumor Initiating Cells (BTIC) retain molecular- subtype plasticity such that treatment drives GBMs away from the proneural (PN) subtype towards a treatment resistant mesenchymal (MES) phenotype. PN is associated with a significantly increased long-term survival compared to the highly resistant MES subtype. Hence, devising GBM therapies that either prevent PN-MES transition or promote transition back from MES-PN would constitute innovation and a paradigm-shift solution, since such therapies do not currently exist and all current efforts have been futile. This proposal provides an innovative and paradigm-shifting solution to the GBM quagmire in that we have identified a novel mechanism of PN-MES reprogramming that we can target and drive GBM molecular subtype plasticity towards a “long- term survival” phenotype. Developing therapies that modulate GBM plasticity towards a “long-term survival” phenotype is our long-term goal. The objective in this application is to understand how BIRC3 and impacted pathways mediate PN-MES reprogramming in GBM. BIRC3 is an inhibitor of apoptosis protein, and we have demonstrated its role in: (i) GBM resistance; (ii) GBM patient outcome/survival, and (iii) upregulation by PI3K and STAT3 signaling. Furthermore, we have identified BIRC3 as a biomarker for the MES subtype in GBM patients and driver of hypoxia-mediated survival in GBM. We now provide new and novel preliminary evidence that BIRC3 promotes PN-MES reprogramming in GBM cell lines and BTIC models. We further provide novel mechanistic evidence that BIRC3 interacts with STAT3 through the BIR1 domain; and that STAT3 phosphorylation enables nuclear translocation of BIRC3 and subsequent downstream activation of MES target genes as a co-transcriptional factor. Hence, there is a strong rationale to examine how BIRC3 influences PN- MES reprogramming in GBM. We submit that BIRC3 and STAT3 heterodimerize and translocate into the nucleus to initiate a transcriptional program that mediates PN-MES reprogramming in GBM; and we hypothesize that inhibition of BIRC3/STAT3 signaling will reverse PN-MES reprogramming in GBM. In Aim 1, we will determine how BIRC3-STAT3 signaling impacts PN-MES reprogramming in GBM. In Aim 2, we will determine if disruption of BIRC-STAT3 signaling in vivo prevents treatment-induced PN-MES reprogramming, sensitizes tumors to therapy and promotes a long-term survival phenotype in GBM. Mechanistic knowledge attained from this proposal could lead to the development of innovative GBM treatment strategies directed against PN-MES reprogramming.

胶质母细胞瘤（GBM）是一种统一致死的癌症替莫唑胺（TMZ）和放疗（RT）。 GBM的二线疗法以及 GBM免疫疗法试验的最新失败进一步强调了GBM中对新范式的强烈需求。 GBM中治疗耐药性的一种假设是，脑肿瘤引发细胞（BTIC）保留分子 - 亚型可塑性使得治疗使GBMS从胸膜（PN）亚型驱逐出治疗抗性间充质（MES）表型。 PN与长期生存显着增加有关与高度抗性的MES亚型相比。因此，设计了预防PN-MES的GBM疗法从MES-PN的过渡或促进过渡将构成创新和范式移位解决方案，由于此类疗法目前不存在，并且所有目前的努力都是徒劳的。该建议提供了 GBM泥浆的创新和范式转移解决方案，因为我们已经确定了一种新型机制 PN-MES重新编程，我们可以靶向并驱动GBM分子亚型可塑性朝着“长术语生存”表型。开发将GBM可塑性调节为“长期生存”的疗法表型是我们的长期目标。此应用程序的目的是了解BIRC3和如何影响途径介导GBM中的PN-MES重编程。 Birc3是凋亡蛋白的抑制剂，我们有展示了其在以下方面的作用：（i）GBM抗性；（ii）GBM患者的结果/生存率，以及（iii）PI3K上调和STAT3信号。此外，我们已经将BIRC3确定为GBM中MES亚型的生物标志物患者和缺氧介导的GBM生存率。我们现在提供新的新型初步证据该BIRC3在GBM细胞系和BTIC模型中促进了PN-MES重编程。我们进一步提供小说 BIRC3通过BIR1域与STAT3相互作用的机械证据；和那个Stat3 磷酸化使BIRC3的核易位和随后的MES靶标的下游激活基因作为共转录因子。因此，有很强的理由来研究Birc3如何影响PN- MES在GBM中重新编程。我们认为Birc3和STAT3异二聚体并转移到核启动转录程序，该程序介导GBM中的PN-MES重编程；还有我们假设抑制BIRC3/STAT3信号传导将在GBM中逆转PN-MES重编程。在AIM 1中，我们将确定BIRC3-STAT3信号如何影响GBM中的PN-MES重编程。在AIM 2中，我们将确定体内BIRC-STAT3信号的破坏是否可以防止治疗诱导的PN-MES重编程，将肿瘤敏感到治疗，并促进GBM中的长期生存表型。机械知识该提案从该提案中得出可能导致创新的GBM治疗策略的发展反对PN-MES重编程。