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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）是一种一致致命的癌症，手术后的中位生存率很低，替莫唑胺（TMZ）和放射治疗（RT）。GBM的二线治疗尝试无效，最近GBM免疫治疗试验的失败进一步强调了对GBM新范例的强烈需要。 GBM中治疗抗性的一个假设是脑肿瘤起始细胞（BTIC）保留分子- 亚型可塑性使得治疗驱使GBM远离前神经（PN）亚型朝向治疗耐药间充质（MES）表型。PN与长期生存率显著增加相关与高耐药MES亚型相比。因此，设计GBM疗法，从MES-PN过渡或促进过渡将构成创新和范式转换解决方案，因为这种疗法目前还不存在，目前的所有努力都是徒劳的。该提案提供了一个一个创新的和范式转变的解决方案，以GBM的泥潭，我们已经确定了一个新的机制 PN-MES重编程，我们可以靶向和驱动GBM分子亚型可塑性向“长- 术语存活”表型。开发调节GBM可塑性以实现“长期生存”的疗法表型是我们的长期目标。本应用程序的目标是了解BIRC 3和通路介导GBM中的PN-MES重编程。BIRC 3是一种凋亡蛋白抑制剂，证实了其在以下方面的作用：（i）GBM抗性;（ii）GBM患者结果/存活，和（iii）PI 3 K的上调 STAT 3信号此外，我们已经确定BIRC 3作为GBM中MES亚型的生物标志物， GBM患者和低氧介导的存活的驱动因素。我们现在提供新的和新颖的初步证据 BIRC 3促进GBM细胞系和BTIC模型中的PN-MES重编程。我们还提供新颖的 BIRC 3通过BIR 1结构域与STAT 3相互作用的机制证据; 磷酸化使BIRC 3的核转位和随后的MES靶的下游活化成为可能基因作为一个共同的转录因子。因此，有很强的理由来研究BIRC 3如何影响PN。 GBM中的MES重编程。我们认为BIRC 3和STAT 3异源二聚体化并易位到核启动转录程序，介导GBM中的PN-MES重编程;并且我们假设BIRC 3/STAT 3信号传导的抑制将逆转GBM中的PN-MES重编程。在目标1中，我们将确定BIRC 3-STAT 3信号传导如何影响GBM中的PN-MES重编程。在目标2中，我们将确定体内BIRC-STAT 3信号传导的破坏是否阻止治疗诱导的PN-MES重编程，使肿瘤对治疗敏感并促进GBM中的长期存活表型。机械知识从这一建议中获得的可能导致创新的GBM治疗策略的发展，对抗PN-MES重编程