Waddell Shelby, Zhao Guannan, Liu Ziping, Chen Hao, Zhang Wenjing, Wang Yaohong, Miller Duane D, Yue Junming, Li Wei
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Gynecology and Obstetrics, Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
J Pharmacol Exp Ther. 2025 Jan;392(1):100006. doi: 10.1124/jpet.124.002298. Epub 2024 Nov 22.
Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, and well tolerated and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and ultimately apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment of ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. SIGNIFICANCE STATEMENT: VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo antitumor and antimetastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.
卵巢癌是最致命的妇科恶性肿瘤，5年生存率约为50%。预后不佳部分归因于转移性疾病以及对紫杉烷等传统化疗药物产生的获得性耐药。秋水仙碱结合位点抑制剂（CBSIs）是紫杉烷类药物颇具吸引力的替代物，因为它们有可能实现口服生物利用度，并克服与长期使用紫杉烷相关的耐药性。VERU-111是最先进的CBSIs之一，具有口服可用性、强效性和良好的耐受性，并且在多个临床前实体瘤模型中显示出良好的疗效。在此，我们首次证明了VERU-111在体外的效力，以及其在原位卵巢癌小鼠模型中抑制肿瘤生长和转移的功效。VERU-111对卵巢癌细胞系具有纳摩尔效力，并强烈抑制集落形成、增殖、侵袭和迁移。VERU-111以浓度依赖性方式破坏微管形成，诱导有丝分裂灾难并最终导致细胞凋亡。VERU-111的疗效与标准化疗药物紫杉醇相当，紫杉醇是目前卵巢癌的一线治疗药物，联合使用紫杉醇+VERU-111治疗未观察到协同作用。在体内，VERU-111显著抑制卵巢肿瘤生长，并完全抑制远处器官转移。总之，这些结果支持VERU-111作为卵巢癌新疗法的潜力，特别是对于晚期转移性疾病。意义声明：VERU-111是一种研究性新药，在体外卵巢癌模型中抑制肿瘤细胞增殖、集落形成和迁移方面与紫杉醇具有相当疗效，并且在原位卵巢癌小鼠模型中具有强大的体内抗肿瘤和抗转移活性。VERU-111全身毒性低，与紫杉醇不同，它具有口服生物利用度，且不是主要药物外排转运蛋白的底物，使其成为基于紫杉烷类治疗的一种有前景且有吸引力的替代物。
