Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, 80523-1620, USA.
Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, 80523, USA.
BMC Vet Res. 2020 Mar 24;16(1):97. doi: 10.1186/s12917-020-02317-3.
Lymphoma is a common cancer in dogs. While most dogs receiving chemotherapy experience remission, very few are cured, and median survival times are generally in the 12-month range. Novel approaches to treatment are unquestionably needed. The Inhibitor of Apoptosis Protein (IAP) family member survivin, which is one of the most commonly overexpressed proteins in human cancer, plays a key role in apoptosis resistance, a major cause of drug-resistant treatment failure. Survivin targeting therapies have shown promise preclinically; however, none have been evaluated in dogs to date. The goal of the current study was to determine the safety and pharmacodynamic effects of systemic administration of the anti-survivin locked nucleic acid antisense oligonucleotide EZN-3042 in dogs with lymphoma.
We performed a prospective phase-I clinical trial in dogs with biopsy-accessible peripheral nodal lymphoma. Eighteen dogs were treated with EZN-3042 as a 2-h IV infusion at 5 dose levels, from 3.25 to 8.25 mg/kg twice weekly for 3 treatments. No dose-limiting toxicities were encountered. Reduction in tumor survivin mRNA and protein were observed in 3 of 5 evaluable dogs at the 8.25 mg/kg dose cohort.
In conclusion, reduced survivin expression was demonstrated in lymphoma tissues in the majority of dogs treated with EZN-3042 at 8.25 mg/kg twice weekly, which was associated with minimal adverse effects. This dose may be used in future studies of EZN-3042/chemotherapy combinations in dogs with spontaneous lymphoma and other cancers.
淋巴瘤是犬类常见的癌症。尽管大多数接受化疗的犬类都会经历缓解期，但很少有犬类被治愈，中位生存时间通常在 12 个月左右。因此，毫无疑问需要采用新的治疗方法。凋亡抑制蛋白（IAP）家族成员 survivin 是人类癌症中表达最为普遍的蛋白之一，它在凋亡抵抗中发挥着关键作用，而凋亡抵抗是导致药物治疗失败的主要原因。Survivin 靶向治疗在临床前研究中显示出了一定的前景；然而，迄今为止，尚无研究将其应用于犬类。本研究的目的是确定全身性给予抗 survivin 的锁核酸反义寡核苷酸 EZN-3042 治疗犬淋巴瘤的安全性和药效学影响。
我们对可进行活检的外周淋巴结淋巴瘤犬进行了一项前瞻性的 I 期临床试验。18 只犬以 5 个剂量水平（3.25 至 8.25mg/kg）接受 EZN-3042 治疗，每周两次静脉输注 2 小时，共 3 个疗程。未发现剂量限制毒性。在 8.25mg/kg 剂量组的 5 只可评估犬中，有 3 只观察到肿瘤 survivin mRNA 和蛋白减少。
综上所述，在大多数接受 EZN-3042 8.25mg/kg 每周两次治疗的犬中，淋巴瘤组织中 survivin 的表达减少，这与最小的不良反应相关。该剂量可能用于未来研究 EZN-3042/化疗联合治疗犬自发性淋巴瘤和其他癌症。
