Verteporfin as a YAP/TAZ inhibitor for treatment of glioblastoma

项目摘要/摘要 胶质母细胞瘤是由胶质细胞及其前体细胞组成的肿瘤，是最致命的原发肿瘤之一。 脑癌，用目前的治疗方法是无法治愈的。临床上迫切需要未得到满足的新疗法。 适用于GBM及相关的高级别恶性胶质瘤。GBM的致瘤性通常是由 受体酪氨酸激酶(RTK)，如EGFR，以及PI-3激酶(PI3K)信号通路。通过我们的 团队的合作翻译研究工作，我们发现YAP和TAZ转录共同- 激活剂，河马途径的效应器，通过TEAD辅助因子促进基因表达，是河马病毒感染的关键驱动因素 EGFR致癌信号下游的GBM致瘤性。在测试YAP/TAZ功能时，我们的团队 发现FDA批准的药物维替普芬(VP)对YAP/TAZ的药理抑制作用有效 特异性地诱导EGFR突变/扩增的GBM细胞生长停滞和细胞死亡，但保持正常 神经干细胞。VP通过阻断YAP和TAZ与TEAD共激活剂的联系来抑制YAP和TAZ，TEAD共激活剂与 DNA我们发现VP特异性地抑制YAP/TAZ转录靶标的表达，包括EGFR， VP治疗显著提高了同种异种GBM移植模型和小鼠的存活率 遗传性GBM模型。我们的结果导致我们对复发的GBM患者进行了VP的0期临床试验， 这表明VP在GBM肿瘤细胞中被吸收，VP引起的变化与抑制一致 YAP/TAZ函数。基于我们的结果，我们已经启动了VP的1/2期临床试验，以确定最佳方案 GBM患者应用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VP临床试验资本化，我们建议1)确定YAP/TAZ靶基因，这些基因是 在GBM进展中依赖YAP/TAZ的表观遗传学基础，目的2)确定适应机制 临床前GBM模型中YAP/TAZ抑制和维替泊芬抵抗以确定表观基因组学 允许GBM干细胞逃避治疗靶点的特定适应，以及Aim 3)评估其影响 维替普芬联合抗血管生成治疗对小鼠肾小管间充质干细胞和肿瘤微环境的影响 免疫活性小鼠模型和我们临床试验中的人类患者标本中的VP。更广泛的 该项目的目标是建立针对GBM中YAP/TAZ活性的治疗基础和策略 改用VP治疗基底膜。

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.