Verteporfin as a YAP/TAZ inhibitor for treatment of glioblastoma

维替泊芬作为 YAP/TAZ 抑制剂治疗胶质母细胞瘤

• 批准号: 10737348
• 负责人: Renee D Read
• 金额: $ 57.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737348
• 关键词: Adhesions; Adult; Angiogenesis Inhibitors; Animal Model; Apoptosis; Binding; Brain; Brain Neoplasms; Cell Communication; Cell Death; Cell Survival; Cell physiology; Cells; Clinical; Clinical Trials; DNA; Data; Dependence; Dose; Drug Targeting; Edema; Epidermal Growth Factor Receptor; Epigenetic Process; FDA approved; Fluorescence Spectrometry; Gene Expression; Genes; Genetic; Genetic Transcription; Glioblastoma; Glioma; Goals; Growth; Human; Immunocompetent; Immunosuppression; Liposomes; Macular degeneration; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Mass Spectrum Analysis; Mediating; Metabolism; Modeling; Mus; Mutation; Neoplasms; Neuroglia; Oncogenic; Organoids; PIK3CG gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase 0 Clinical Trial; Phase I/II Clinical Trial; Phosphotransferases; Primary Brain Neoplasms; Process; Proliferating; Proteins; Proto-Oncogene Proteins c-myc; Receptor Protein-Tyrosine Kinases; Recurrence; Resistance; Signal Pathway; Signal Transduction; Specimen; Stable Disease; Testing; Therapeutic; Therapeutic Effect; Transcription Coactivator; Translational Research; Tumor Promotion; Tumor Stem Cells; Tumorigenicity; Vascular Endothelial Growth Factors; Verteporfin; Visualization; Xenograft Model; absorption; angiogenesis; bevacizumab; blood-brain barrier crossing; c-myc Genes; clinical trial participant; cofactor; efficacy testing; epigenomics; inhibitor; insight; liposomal formulation; migration; mouse genetics; mouse model; mutant; neoplastic cell; nerve stem cell; neural; overexpression; pharmacologic; pre-clinical; programs; protein expression; response; response biomarker; self-renewal; stem cell self renewal; stem cells; therapeutic evaluation; therapeutic target; transcriptomics; tumor; tumor diagnosis; tumor microenvironment; tumor progression; uptake

PROJECT SUMMARY/ABSTRACT Glioblastomas (GBMs), neoplasms composed of glial cells and their precursors, are among the deadliest primary brain cancers, and are incurable with current therapies. There is an urgent unmet clinical need for new treatments for GBM and related high-grade malignant gliomas. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Through our team’s collaborative translational research efforts, we discovered that the YAP and TAZ transcription co- activators, effectors of the Hippo pathway that promote gene expression via TEAD co-factors, as key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling. In testing YAP/TAZ function, our team discovered that pharmacologic inhibition of YAP/TAZ with the FDA-approved drug verteporfin (VP) potently and specifically provokes growth arrest and cell death of EGFR-mutant/amplified GBM cells, but spares normal neural stem cells. VP inhibits YAP and TAZ by blocking their association with TEAD co-activators, which bind to DNA. We found that VP specifically suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and that VP treatment conferred significant survival benefits in an orthotopic GBM xenograft model and a mouse genetic GBM model. Our results led us to perform a phase 0 clinical trial of VP in patients with recurrent GBM, which showed that VP is absorbed in GBM tumor cells and that VP induced changes consistent with inhibition of YAP/TAZ function. Based on our results, we have initiated a phase 1/2 clinical trial of VP to determine optimal dosing of VP in GBM patients. Here, we propose to investigate the therapeutic potential of YAP/TAZ inhibition and to capitalize our VP clinical trials, we propose to Aim 1) Identify YAP/TAZ target genes that underlie the epigenetic basis of YAP/TAZ dependency in GBM progression, Aim 2) Determine mechanisms of adaptation to YAP/TAZ inhibition and verteporfin resistance in pre-clinical GBM models in order to identify epigenomic adaptations specific that allow GBM stem cells to escape therapeutic targeting, and Aim 3) Evaluate the impact of verteporfin combined with anti-angiogenic therapies on GBM stem cells and the tumor microenvironment in immunocompetent mouse models and in specimens from human patients on our clinical trial of VP. The broader goals of this project are to establish a basis and strategies for therapeutic targeting YAP/TAZ activity in GBM using repurposed VP as a treatment for GBM.

项目摘要/摘要 胶质母细胞瘤（GBM），由神经胶质细胞及其前体组成的肿瘤是最致命的主要主要 脑癌，并且可以治疗当前的疗法。紧急未满足新治疗的临床需求 用于GBM和相关的高级恶性神经胶质瘤。 GBM肿瘤性通常是由遗传畸变驱动的 受体酪氨酸激酶（RTK），例如EGFR和PI-3激酶（PI3K）信号通路。通过我们的 团队的合作转化研究工作，我们发现YAP和TAZ转录共同 激活剂，河马途径的效果，该途径通过Tead coactor促进基因表达，作为关键驱动因素 GBM致癌性EGFR信号下游的肿瘤性。在测试YAP/TAZ功能时，我们的团队 发现使用FDA批准的药物verteporfin（VP）对YAP/TAZ的药物抑制可能会抑制 特别挑衅EGFR突变/扩增的GBM细胞的生长停滞和细胞死亡，但挽救了正常的 神经干细胞。 VP通过阻止其与Tead共激活因子的关联来抑制YAP和TAZ，并结合 脱氧核糖核酸。我们发现，VP特异性抑制了YAP/TAZ转录靶标的表达，包括EGFR， 该VP治疗在原位GBM特征模型和小鼠中赋予了显着的生存优势 遗传GBM模型。我们的结果使我们对复发性GBM患者进行了VP的0期临床试验， 这表明VP在GBM肿瘤细胞中吸收，并且VP诱导的变化与抑制一致 YAP/TAZ功能的功能。根据我们的结果，我们启动了VP的1/2阶段临床试验，以确定最佳 GBM患者中VP的剂量。在这里，我们建议研究YAP/TAZ抑制的治疗潜力 为了使我们的副总裁临床试验资本，我们建议目标1）确定YAP/TAZ靶基因的基因 GBM进展中YAP/TAZ依赖性的表观遗传基础，目标2）确定适应机制 临床前GBM模型中的YAP/TAZ抑制和Verteporfin抗性，以鉴定表观基因组学 适应特定的，允许GBM干细胞逃脱治疗靶向的特定适应，目标3）评估影响 Verteporfin与GBM干细胞上的抗血管生成疗法和肿瘤微环境结合 在我们的VP临床试验中，免疫功能的小鼠模型和人类患者的标本中。更广泛的 该项目的目标是为GBM中的YAP/TAZ活动建立基础和策略 使用重新利用的VP作为GBM的治疗方法。