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

• 批准号: 10058679
• 负责人: Arnold Etame
• 金额: $ 24.71万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058679
• 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; Modeling; Molecular; Mutation; N-terminal; Neurosurgeon; Nuclear Translocation; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phosphorylation; Positioning Attribute; 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; outcome forecast; prevent; programs; response; stem cells; survival outcome; temozolomide; therapy development; therapy resistant; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor growth; ubiquitin-protein ligase

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)是一种完全致命的癌症，手术后的中位存活率很低。 替莫唑胺(TMZ)和放射治疗(RT)。治疗GBM的二线疗法以及 最近GBM免疫治疗试验的失败进一步强调了对GBM新范式的强烈需求。 胶质瘤耐药的一个假说是脑肿瘤起始细胞(BTIC)保留分子- 亚型可塑性：治疗使GBM从原神经(PN)亚型向治疗方向发展 耐药间充质(MES)表型。PN与显著增加的长期存活率有关 与高抗性的MES亚型相比。因此，设计GBM疗法既可以预防PN-MES 从MES-PN过渡或促进向后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。这项建议提供了一个 针对GBM泥潭的创新和范式转换解决方案，因为我们确定了一种新的机制 的PN-MES重新编程，我们可以靶向和驱动GBM分子亚型的可塑性走向“长- “长期生存”的表型。开发调节GBM可塑性以实现“长期生存”的治疗方法 表型是我们的长期目标。本应用程序的目标是了解BIRC3和 通路介导了GBM中的PN-MES重编程。BIRC3是一种凋亡抑制蛋白，我们有 证实了它在以下方面的作用：(I)基底膜抵抗；(Ii)基底膜患者的预后/存活率；以及(Iii)PI3K上调 和STAT3信令。此外，我们已经确定BIRC3是GBM中MES亚型的生物标志物 低氧介导的基底膜存活的患者和驱动因素。我们现在提供新的和新颖的初步证据 BIRC3促进GBM细胞系和BTIC模型中的PN-MES重编程。我们进一步提供新颖的 BIRC3通过BIR1结构域与STAT3相互作用的机械证据；以及STAT3 磷酸化使BIRC3的核转位和随后的MES靶向下游激活 基因作为一种共转录因子。因此，有一个强有力的理由来研究BIRC3如何影响Pn- 在GBM中对MES进行重新编程。我们提出BIRC3和STAT3异源二聚并移位到 细胞核启动转录程序，介导GBM中的PN-MES重新编程；我们 假设抑制BIRC3/STAT3信号将逆转GBM中的PN-MES重编程。在目标1中， 我们将确定BIRC3-STAT3信号如何影响GBM中的PN-MES重新编程。在目标2中，我们将 确定体内BIRC-STAT3信号的中断是否阻止了治疗诱导的PN-MES重编程， 使肿瘤对治疗敏感，并促进GBM的长期生存表型。机械论知识 从这项提议中获得的成果可能导致开发有针对性的创新的GBM治疗策略 对抗PN-MES重新编程。