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Targeting Metastasis in Head and Neck Squamous Cell Carcinoma Using Follistatin mRNA Lipid Nanoparticles
Vladislav Grigoriev1, Tetiana Korzun1,2,3, Abraham S Moses1
1Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon 97201, United States.
Abstract:
Metastatic progression significantly reduces survival rates and complicates treatment strategies in various cancers. Our study introduces an mRNA therapy for metastasis inhibition by targeting activin A overexpression, a pivotal driver of metastasis and cachexia. Utilizing follistatin mRNA lipid nanoparticles, we effectively downregulated activin A both locally in the tumor environment and systemically. This led to a reduction in tumor burden and suppression of metastatic spread in a murine head and neck squamous cell carcinoma model. Treated mice exhibited minimal metastatic occurrence compared to controls. Additionally, our therapy preserved the cross-sectional area of muscle fibers and adipose tissues, combating the muscle and fat wasting typically observed in cancer-associated cachexia. The therapy also demonstrated a favorable safety profile, underscoring its potential for clinical translation. By integrating metastasis-suppressing and cachexia-alleviating mechanisms, our approach represents a promising advancement in comprehensive cancer management. Considering the widespread upregulation of activin A in many cancer types, our therapy holds considerable potential for application across a broad spectrum of oncologic treatments.
Insights
This study developed an mRNA therapy targeting activin A to inhibit cancer metastasis and cachexia. The novel treatment reduced tumor burden, suppressed metastasis, and preserved muscle mass in preclinical models.
Area of Science:
- Oncology
- Molecular Therapy
- Cancer Biology
Background:
- Metastatic progression is a major cause of cancer mortality and treatment challenges.
- Activin A overexpression drives both cancer metastasis and cachexia.
- Current treatments often fail to address both metastasis and cachexia concurrently.
Purpose of the Study:
- To develop and evaluate an mRNA therapy targeting activin A for inhibiting metastasis and cachexia.
- To assess the efficacy of follistatin mRNA lipid nanoparticles in downregulating activin A.
- To investigate the impact of this therapy on tumor burden, metastatic spread, and cancer-associated cachexia.
Main Methods:
- Utilized follistatin mRNA encapsulated in lipid nanoparticles for delivery.
- Administered therapy to a murine model of head and neck squamous cell carcinoma.
- Assessed tumor burden, metastatic occurrence, muscle fiber cross-sectional area, and adipose tissue mass.
Main Results:
- Successfully downregulated activin A both locally and systemically.
- Achieved significant reduction in tumor burden and suppressed metastatic spread.
- Preserved muscle fiber and adipose tissue integrity, mitigating cachexia.
- Demonstrated a favorable safety profile in the preclinical model.
Conclusions:
- Follistatin mRNA lipid nanoparticle therapy effectively inhibits cancer metastasis and cachexia.
- The dual mechanism of action offers a promising strategy for comprehensive cancer management.
- Broad potential for clinical translation across various cancer types due to widespread activin A upregulation.
