Effects of immunization against PCSK9 in an experimental model of breast cancer

Abstract

Introduction: Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an efficient strategy for lowering low-density lipoprotein cholesterol (LDL-C). There are, however, scant data on the efficacy and safety of PCSK9 inhibitors in non-cardiovascular diseases, particularly cancer. The present study aimed to evaluate the effect of PCSK9 inhibition using a nanoliposomal antiPCSK9 vaccine on cancer behavior and endpoints in mice bearing breast tumor. Material and methods: To induce antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine absorbed on 0.4% alum adjuvant was used. To induce tumor, BALB/c mice were subcutaneously inoculated with 4T1 breast carcinoma cells. After the tumor mass was palpable (approximately 10 mm3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) combination of vaccine and Doxil, and (4) Doxil (positive control) group. Vaccine was subcutaneously administered to mice four times at 2-week intervals. Two weeks after the last administration, the vaccinated and non-vaccinated mice were subcutaneously inoculated with 4T1 breast carcinoma cells. To evaluate therapeutic efficacy, mouse body weight, tumor size, and survival were monitored every other day for 60 days. Results: The nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in BALB/c mice, thereby decreasing plasma levels of PCSK9 and inhibiting its function. Tumor size analysis showed that time to reach endpoint (TTE) of the vaccine, combination, Doxil, and control groups was 47 ±10, 57 ±4, 60 ±4 and 39 ±9 days, respectively. Rate of tumor growth in vaccine, combination and Doxil groups was decreased by 21%, 48% and 53%, respectively, compared to the control group. Lifespan was increased by 4.2% in the vaccine group, compared with the control group. Additionally, the survival in the combination and Doxil groups was significantly higher than the vaccine and control groups. Conclusions: Our results revealed that PCSK9 inhibition may moderately improve breast cancer outcomes while having no harmful effects in tumor-bearing mice.