Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases in the United States. TNBC has poorer overall prognosis relative to other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. Taxanes like paclitaxel are standard chemotherapies that stabilize microtubules, but their clinical efficacy is often limited by drug resistance and neurotoxicities. We evaluated the preclinical efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, in TNBC models. VERU-111 showed potent cytotoxicity against TNBC cell lines, inducing apoptosis and cell-cycle arrest in a concentration-dependent manner. VERU-111 also efficiently inhibited colony formation, cell migration, and invasion. Orally administered VERU-111 inhibited MDA-MB-231 xenograft growth in a dose-dependent manner, with similar efficacies to paclitaxel, but without acute toxicity. VERU-111 significantly reduced metastases originating from the mammary fat pad into lung, liver, and kidney metastasis in an experimental metastasis model. Moreover, VERU-111, but not paclitaxel, suppressed growth of luciferase-labeled, taxane-resistant, patient-derived metastatic TNBC tumors. In this model, VERU-111 repressed growth of preestablished axillary lymph node metastases and lung, bone, and liver metastases at study endpoint, whereas paclitaxel enhanced liver metastases relative to vehicle controls. Collectively, these studies strongly suggest that VERU-111 is not only a potent inhibitor of aggressive TNBC phenotypes, but it is also efficacious in a taxane-resistant model of metastatic TNBC. Thus, VERU-111 is a promising new generation of tubulin inhibitor for the treatment of TNBC and may be effective in patients who progress on taxanes. Results presented in this study demonstrate the efficacy of VERU-111 in vivo and provide strong rationale for future development of VERU-111 as an effective treatment for metastatic breast cancer.

中文翻译：

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一种可口服的微管蛋白抑制剂 VERU-111，可抑制三阴性乳腺癌肿瘤的生长和转移并绕过紫杉烷抗性

三阴性乳腺癌 (TNBC) 约占美国乳腺癌病例的 15%。由于对常规化学疗法的快速耐药性和内脏转移风险增加，TNBC 相对于其他分子亚型的总体预后较差。紫杉烷类紫杉醇是稳定微管的标准化学疗法，但其临床疗效通常受到耐药性和神经毒性的限制。我们在 TNBC 模型中评估了一种新型、有效和口服生物可利用的微管蛋白抑制剂 VERU-111 的临床前疗效。VERU-111 对 TNBC 细胞系显示出有效的细胞毒性，以浓度依赖性方式诱导细胞凋亡和细胞周期停滞。VERU-111 还有效抑制集落形成、细胞迁移和侵袭。口服 VERU-111 以剂量依赖性方式抑制 MDA-MB-231 异种移植物的生长，具有与紫杉醇相似的功效，但没有急性毒性。在实验性转移模型中，VERU-111 显着减少了源自乳腺脂肪垫到肺、肝和肾转移的转移。此外，VERU-111（而非紫杉醇）抑制了荧光素酶标记的、耐紫杉烷的、患者来源的转移性 TNBC 肿瘤的生长。在该模型中，VERU-111 在研究终点抑制预先确定的腋窝淋巴结转移以及肺、骨和肝转移的生长，而相对于载体对照，紫杉醇增强了肝转移。总的来说，这些研究强烈表明 VERU-111 不仅是侵袭性 TNBC 表型的有效抑制剂，但它在紫杉烷抗性转移性 TNBC 模型中也有效。因此，VERU-111 是一种有前途的新一代微管蛋白抑制剂，用于治疗 TNBC，可能对紫杉类药物进展的患者有效。本研究中呈现的结果证明了 VERU-111 的体内功效，并为未来将 VERU-111 开发为转移性乳腺癌的有效治疗方法提供了强有力的理论基础。