Sabizabulin, a Potent Orally Bioavailable Colchicine Binding Site Agent, Suppresses HER2+ Breast Cancer and Metastasis.
Sabizabulin, a Potent Orally Bioavailable Colchicine Binding Site Agent, Suppresses HER2+ Breast Cancer and Metastasis.
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在HER2+乳腺癌模型中，萨比布林抑制肿瘤细胞生长、细胞迁移和集落形成，并诱导细胞死亡。在HER2+患者来源的异种移植(PDX)模型中，Sabizumin在抑制HER2+异种移植生长和抑制肺转移方面与紫杉醇相当。沙比布林是一种很有前途的口服药物，可以替代紫杉烷，用于乳腺癌患者的微管蛋白靶向治疗，包括HER2+乳腺癌分子亚型。HER2+乳腺癌占所有乳腺癌病例的15%。目前HER2+转移性乳腺癌的一线治疗依赖于靶向抗体、曲妥珠单抗和pertuzumab，以及紫杉烷类微管抑制剂(紫杉醇或多西紫杉醇)。众所周知，紫杉烷的临床疗效受到化疗耐药以及血液和神经毒性的发展的限制。秋水仙素结合位点抑制剂(CBSI)是一类很有前途的紫杉烷类替代药物。Sabizumin(以前称为Veru-111)是一种有效的CBSI，它克服了P-gp介导的紫杉烷耐药，具有口服生物利用度，并抑制三阴性乳腺癌(TNBC)的肿瘤生长和远处转移。在这里，我们展示了萨比布林治疗HER2+乳腺癌的疗效。在体外，沙比布林以浓度依赖的方式抑制HER2+乳腺癌细胞株的增殖，抑制克隆形成，诱导细胞凋亡。在体内，萨比布林在BT474(ER+/PR+/HER2+)异种移植模型和HER2+(ER-/PR-)转移性患者来源的异种移植(PDX)模型中抑制乳腺肿瘤的生长。我们证明沙比布林是HER2+乳腺癌靶向微管蛋白的一种有前景的替代药物，具有与紫杉醇相似的抗转移疗效，但具有口服生物利用度和比紫杉烷低的毒性优势。
The sabizabulin agent represses tumor cell growth, cell migration, and colony formation, and induces cell death in HER2+ breast cancer models. Sabizabulin is comparable to paclitaxel to suppress HER2+ xenograft growth and to inhibit lung metastasis in a HER2+ patient-derived xenograft (PDX) model. Sabizabulin is a promising orally available agent as an alternative to taxanes to target tubulin in breast cancer patients, including the HER2+ breast cancer molecular subtype. HER2+ breast cancer accounts for 15% of all breast cancer cases. Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). It is well known that the clinical efficacy of taxanes is limited by the development of chemoresistance and hematological and neurotoxicities. The colchicine-binding site inhibitors (CBSIs) are a class of promising alternative agents to taxane therapy. Sabizabulin (formerly known as VERU-111) is a potent CBSI that overcomes P-gp-mediated taxane resistance, is orally bioavailable, and inhibits tumor growth and distant metastasis in triple negative breast cancer (TNBC). Herein, we demonstrate the efficacy of sabizabulin in HER2+ breast cancer. In vitro, sabizabulin inhibits the proliferation of HER2+ breast cancer cell lines with low nanomolar IC50 values, inhibits clonogenicity, and induces apoptosis in a concentration-dependent manner. In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes.
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作者：
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