Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
Mol Cancer Ther. 2020 Feb;19(2):348-363. doi: 10.1158/1535-7163.MCT-19-0536. Epub 2019 Oct 23.
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 and provide strong rationale for future development of VERU-111 as an effective treatment for metastatic breast cancer.
三阴性乳腺癌（TNBC）约占美国乳腺癌病例的 15%。与其他分子亚型相比，由于对常规化疗药物的耐药性迅速发生，并且内脏转移的风险增加，TNBC 的总体预后较差。紫杉醇等紫杉烷类药物是稳定微管的标准化疗药物，但由于耐药性和神经毒性，其临床疗效往往受到限制。我们评估了一种新型、有效且口服生物可利用的微管抑制剂 VERU-111 在 TNBC 模型中的临床前疗效。VERU-111 对 TNBC 细胞系表现出强大的细胞毒性，以浓度依赖性方式诱导细胞凋亡和细胞周期停滞。VERU-111 还能有效抑制集落形成、细胞迁移和侵袭。口服给予 VERU-111 以剂量依赖性方式抑制 MDA-MB-231 异种移植物的生长，与紫杉醇的疗效相当，但无急性毒性。VERU-111 显著减少了来自乳腺脂肪垫的转移，减少了肺、肝和肾转移在实验性转移模型中的转移。此外，与紫杉醇相比，VERU-111 不仅抑制了生长，而且还抑制了生长。对肿瘤进行了luciferase 标记、紫杉烷耐药、患者来源的转移性 TNBC 肿瘤。在该模型中，与载体对照相比，VERU-111 在研究终点时抑制了腋窝淋巴结转移和肺、骨和肝转移的生长，而紫杉醇增强了肝转移。总的来说，这些研究强烈表明，VERU-111 不仅是一种有效的侵袭性 TNBC 表型抑制剂，而且在转移性 TNBC 的紫杉烷耐药模型中也有效。因此，VERU-111 是一种治疗 TNBC 的新一代微管抑制剂，可能对紫杉烷耐药的患者有效。本研究结果表明 VERU-111 的疗效，并为 VERU-111 作为转移性乳腺癌有效治疗药物的进一步开发提供了强有力的依据。
