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：
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
项目类别：
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

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) 是一种均致死性的癌症，术后中位生存率很低，替莫唑胺 (TMZ) 和放射治疗 (RT) 尝试治疗 GBM 和二线疗法均无效。最近 GBM 免疫治疗试验的失败进一步凸显了 GBM 对新范例的强烈需求。 GBM 治疗抵抗的一种假设是脑肿瘤起始细胞 (BTIC) 保留分子- 亚型可塑性，使得治疗可驱使 GBM 从原神经 (PN) 亚型转向治疗耐药间充质（MES）表型与长期生存率显着增加相关。与高度耐药的 MES 亚型相比，因此，设计可以预防 PN-MES 的 GBM 疗法。过渡或促进从 MES-PN 过渡回来将构成创新和范式转变解决方案，由于目前尚不存在此类疗法，并且当前的所有努力都是徒劳的，因此该提案提供了一种方法。 GBM 困境的创新和范式转变解决方案，因为我们已经确定了一种新颖的机制 PN-MES 重编程，我们可以针对并驱动 GBM 分子亚型可塑性走向“长期开发调节 GBM 可塑性以实现“长期生存”的疗法。表型是我们的长期目标，本应用的目标是了解 BIRC3 的影响。 BIRC3 是细胞凋亡蛋白的抑制剂，介导 GBM 中的 PN-MES 重编程。其在以下方面的作用：(i) GBM 耐药；(ii) GBM 患者预后/生存，以及 (iii) PI3K 上调此外，我们已将 BIRC3 确定为 GBM 中 MES 亚型的生物标志物。我们现在提供了新的初步证据。 BIRC3 促进 GBM 细胞系和 BTIC 模型中的 PN-MES 重编程。 BIRC3 通过 BIR1 结构域与 STAT3 相互作用的机制证据；磷酸化使 BIRC3 发生核转位并随后激活 MES 靶标的下游因此，有充分的理由来研究 BIRC3 如何影响 PN-。我们认为 BIRC3 和 STAT3 异二聚化并易位到 GBM 中。细胞核启动介导 GBM 中 PN-MES 重编程的转录程序；在目标 1 中，抑制 BIRC3/STAT3 信号传导将逆转 GBM 中的 PN-MES 重编程。我们将确定 BIRC3-STAT3 信号传导如何影响 GBM 中的 PN-MES 重编程。确定体内 BIRC-STAT3 信号传导的破坏是否会阻止治疗诱导的 PN-MES 重编程，使肿瘤对治疗敏感并促进 GBM 的长期生存表型。从该提案中获得的成果可能会导致针对 GBM 的创新治疗策略的开发反对 PN-MES 重新编程。