Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma

Abstract

Background: 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. Results: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. Conclusions: 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. BackgroundNon-Hodgkin lymphoma (NHL) is the 7th most common cancer in humans, accounting for approximately 65,000 cases per year [1]. It is the fifth most common, and second fastest growing, cause of human cancer mortality [2]. Likewise, lymphoma is one of the most common cancers encountered in dogs [3]. Both human and canine NHL are characterized by a high likelihood of response to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based chemotherapy; however, 30% of humans and 95% of dogs and will eventually die as a result of drug-resistant relapse, [1,[4][5][6][7] demonstrating that new therapeutic approaches are needed.The dog is a very useful model for the study of human NHL, given remarkable similarities in histology, biology and gene-expression. This includes very similar gross and histological appearance, conserved patterns of organ involvement, comparable prognostic factors, and analogous dysregulation of cell signaling and growth regulation pathways [3,[8][9][10][11][12]. Owing to the relatively compressed time course of disease progression of lymphoma (and cancer in general) in dogs versus humans, the immunocompetence of these patients, and the spontaneous nature of the disease, the study of strategies for chemosensitization can be accomplished

Comparative Cancer Cell Signaling in Muscle-Invasive Urothelial Carcinoma of the Bladder in Dogs and Humans

“…In 2017, a study comparing canine tumors of different origins (epithelial, mesenchymal and round-cell tumors) showed that survivin was significantly increased in malignant versus benign tumors (p < 0.05) at the transcriptional level [64]. Finally, in 2020, the survivin inhibitor EZN-3042 was shown to be well-tolerated in a phase I clinical trial of dogs with lymphoma, opening new avenues for the clinical targeting of this protein in veterinary oncology [65].…”