Preclinical efficacy of PR115002, a novel sortilin-targeting peptide-drug conjugate, in platinum-resistant ovarian cancer.

Abstract

e17559 Background: Approximately 70%-80% of individuals diagnosed with ovarian cancer (OC) experience disease recurrence, with a significant proportion ultimately developing resistance to platinum-based therapies following multiple recurrences. Presently, platinum resistance represents a significant challenge that adversely impacts the survival rates of patients with OC. Sortilin, referred to as neurotensin receptor-3, is implicated in various functions related to intracellular trafficking and the sorting of diverse ligands. Notably, an elevated expression of sortilin has been documented in OC. Methods: Platinum-resistant cell lines were employed to investigate cellular uptake, drug delivery, and cytotoxicity. To evaluate the effectiveness of PR115002, a sortilin-targeting peptide-drug conjugate, in platinum-resistant OC, murine models were utilized to study pharmacokinetics, efficacy, and toxicity. Female Balb/c nude mice, aged 6-8 weeks, were subjected to intracranial implantation of A2780cis and SK-OV-3 cells. After 10 days post-implantation, the subjects received weekly intravenous injections of either a vehicle or PR115002 at dosages of 1 mg/kg, 3 mg/kg, and 5 mg/kg, with the treatment regimen extending over 28 days. Results: The peptide component of PR115002 exhibited a binding affinity of approximately 4 nM for human sortilin, as determined by SPR experiments. In comparison, the binding affinity of sortilin for its substrate neurotensin was found to be nearly 258 nM. In the cells with high sortilin levels, PR115002 demonstrated a significant cellular uptake, a phenomenon that was absent in the cells with low sortilin levels. In platinum-resistant A2780cis and SK-OV-3 cell lines, PR115002 displayed considerable cytotoxicity, with IC50 values of about 1 nM and 3 nM, respectively. Furthermore, the assessment of PR115002’s efficacy in vivo revealed a substantial inhibition of tumor growth exceeding 95% at a dosage of 5 mg/kg in platinum-resistant OC models, including those with low and very low sortilin expression levels. The administration of PR115002 at a dosage of 5 mg/kg every week was found to be well tolerated, exhibiting minimal indications of significant toxicities or weight loss in the animals. Conclusions: The in vitro findings indicated that PR115002 exhibited specific binding affinity for human sortilin and displayed significant cytotoxicity against cell lines resistant to platinum-based therapies. Additionally, the in vivo results revealed the therapeutic efficacy of PR115002 in the context of platinum-resistant OC. Collectively, these findings provide a strong rationale for the continued development of PR115002 for use in patients with platinum-resistant OC.