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Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
Effects of immunization against PCSK9 in an experimental model of breast cancer
Amir Abbas Momtazi-Borojeni1,2, Maryam Ebrahimi Nik3, Mahmoud Reza Jaafari4,5
1Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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.
Insights
PCSK9 inhibition using a novel nanoliposomal vaccine showed potential in improving breast cancer outcomes in mice. This approach reduced tumor growth and enhanced survival without apparent adverse effects, suggesting a new therapeutic avenue.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition effectively lowers LDL-C.
- Limited data exist on PCSK9 inhibitors' efficacy and safety in non-cardiovascular diseases, especially cancer.
- This study investigates PCSK9 inhibition's impact on breast cancer using a nanoliposomal vaccine.
Purpose of the Study:
- To evaluate the effect of PCSK9 inhibition via a nanoliposomal vaccine on breast tumor behavior and endpoints in mice.
- To assess the safety and efficacy of this novel therapeutic strategy.
Main Methods:
- A nanoliposomal anti-PCSK9 vaccine with alum adjuvant was used to induce antibodies in vivo.
- 4T1 breast carcinoma cells were inoculated in BALB/c mice to establish tumors.
- Mice were randomized into four groups: PBS, vaccine, vaccine + Doxil, and Doxil, with treatments administered over 60 days.
Main Results:
- The vaccine successfully induced anti-PCSK9 antibodies, reducing PCSK9 levels and function.
- Tumor growth rate decreased by 21% in the vaccine group, 48% in the combination group, and 53% in the Doxil group compared to controls.
- Lifespan increased by 4.2% in the vaccine group, with significant survival benefits in the combination and Doxil groups.
Conclusions:
- PCSK9 inhibition using a nanoliposomal vaccine may offer moderate improvements in breast cancer outcomes.
- The treatment demonstrated no harmful effects in tumor-bearing mice.
- Further research into PCSK9 inhibition for cancer therapy is warranted.
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