Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Neurosurgery, Stanford University, Stanford, California, USA.
Neuro Oncol. 2022 May 4;24(5):694-707. doi: 10.1093/neuonc/noab244.
Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of glioma growth in disease progression and recurrence. Here, we use the FDA-approved drug and small molecule Hippo inhibitor Verteporfin (VP) to target YAP-TEAD activity, known to mediate convergent aspects of tumor invasion/metastasis, and assess the drug's efficacy and survival benefit in GBM models.
Up to 8 low-passage patient-derived GBM cell lines with distinct genomic drivers, including 3 primary/recurrent pairs, were treated with VP or vehicle (VEH) to assess in vitro effects on proliferation, migration, invasion, YAP-TEAD activity, and transcriptomics. Patient-derived orthotopic xenograft (PDX) models were used to assess VP's brain penetrance and effects on tumor burden and survival.
VP treatment disturbed YAP/TAZ-TEAD activity; disrupted transcriptome signatures related to invasion, epithelial-to-mesenchymal, and proneural-to-mesenchymal transition, phenocopying TEAD1-knockout effects; and impaired tumor migration/invasion dynamics across primary and recurrent GBM lines. In an aggressive orthotopic PDX GBM model, short-term VP treatment consistently diminished core and infiltrative tumor burden, which was associated with decreased tumor expression of Ki67, nuclear YAP, TEAD1, and TEAD-associated targets EGFR, CDH2, and ITGB1. Finally, long-term VP treatment appeared nontoxic and conferred survival benefit compared to VEH in 2 PDX models: as monotherapy in primary (de novo) GBM and in combination with Temozolomide chemoradiation in recurrent GBM, where VP treatment associated with increased MGMT methylation.
We demonstrate combined anti-invasive and anti-proliferative efficacy for VP with survival benefit in preclinical GBM models, indicating potential therapeutic value of this already FDA-approved drug if repurposed for GBM patients.
胶质母细胞瘤（GBM）仍然是一种基本无法治愈的疾病，因为目前的治疗方法无法针对疾病进展和复发过程中胶质瘤生长的侵袭性。在这里，我们使用美国食品和药物管理局批准的药物和小分子 Hippo 抑制剂 Verteporfin（VP）来靶向 YAP-TEAD 活性，该活性已知介导肿瘤侵袭/转移的趋同方面，并评估该药物在 GBM 模型中的疗效和生存获益。
多达 8 个低传代的患者来源 GBM 细胞系，具有不同的基因组驱动因素，包括 3 个原发性/复发性对，用 VP 或载体（VEH）处理，以评估对增殖、迁移、侵袭、YAP-TEAD 活性和转录组的影响。使用患者来源的原位异种移植（PDX）模型来评估 VP 的脑穿透性及其对肿瘤负担和生存的影响。
VP 治疗扰乱了 YAP/TAZ-TEAD 活性；破坏了与侵袭、上皮间质转化和神经前体向间质转化相关的转录组特征，模拟了 TEAD1 敲除的效果；并损害了原发性和复发性 GBM 系的肿瘤迁移/侵袭动力学。在一种侵袭性的原位 PDX GBM 模型中，短期 VP 治疗一致减少了核心和浸润性肿瘤负担，这与肿瘤中 Ki67、核 YAP、TEAD1 和 TEAD 相关靶标 EGFR、CDH2 和 ITGB1 的表达降低有关。最后，与 VEH 相比，长期 VP 治疗在 2 个 PDX 模型中似乎没有毒性并带来生存获益：作为原发性（新发病）GBM 的单一疗法，以及与替莫唑胺放化疗联合用于复发性 GBM，其中 VP 治疗与增加 MGMT 甲基化相关。
我们在临床前 GBM 模型中证明了 VP 的联合抗侵袭和抗增殖疗效，并带来了生存获益，表明如果将这种已获得美国食品和药物管理局批准的药物重新用于 GBM 患者，可能具有潜在的治疗价值。
