Abstract LB019: Comprehensive therapeutic impact: Follistatin mRNA-loaded lipid nanoparticles halt lung metastases and prolong survival in murine head & neck squamous cell carcinoma

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) poses a significant public health challenge due to its aggressive nature, late-stage diagnosis, and association with cancer-associated cachexia. Activin A (ActA), a member of the TGF-β superfamily, has been implicated in HNSCC pathogenesis and cachexia development. Our study proposes a novel therapeutic approach utilizing follistatin (FST) mRNA-loaded lipid nanoparticles (LNPs) to inhibit activin A and address HNSCC progression and cancer cachexia. We engineered LNPs with pseudouridine-substituted FST mRNA for enhanced stability and translational efficiency. In vitro experiments on murine cell lines demonstrated successful FST protein upregulation and subsequent reduction in ActA expression, particularly in HNSCC cells (7.75 ng/mL ActA levels decreased to 6.12 ng/mL by adding 500ng/mL FST mRNA LNP, p = 0.0184). Scratch assays further indicated decreased cellular mobility (26% increase in open “wound area,” p=0.0029), suggesting potential implications for decreased metastatic behavior. For in vivo validation, C57BL/6 mice bearing MLM3 HNSCC tumors were chosen as the experimental model. Our FST mRNA LNP therapy exhibited tolerability with minimal impact on food intake, body weight, and reactogenic cytokine levels. Comprehensive blood analyses revealed no significant alterations in red blood cell parameters, while liver and spleen samples confirmed successful mRNA delivery and elevated FST protein levels (180-times increase, p = 0.0243) with reduced ActA levels (3-times decrease, p= 0.0467) in the serum. Subcutaneous administration of FST mRNA LNP formulation ipsilateral to MLM3 HNSCC tumors resulted in a significant reduction in tumor size (1.7 times reduction, p=0.0418). Intraperitoneal injections yielded a similar outcome with a significant decrease in tumor burden. Our findings revealed a remarkable and unprecedented outcome: the FST mRNA LNP formulation completely inhibited the development of lung metastases originating from primary MLM3 tumors. Survival analysis demonstrated a significant extension of the lifespan of treated mice compared to control groups, emphasizing the therapeutic efficacy of the FST mRNA LNP formulation in preventing lung metastatic spread. Notably, the administration of FST mRNA LNP demonstrated a significant muscle-sparing effect in the context of cancer-associated cachexia. In conclusion, our study introduces a novel and safe therapeutic strategy for HNSCC, leveraging LNPs to deliver FST mRNA for ActA inhibition. This approach holds promise for future clinical applications, addressing the dual challenges of HNSCC progression and cancer-associated cachexia. Citation Format: Oleh Taratula, Tetiana Korzun, Antony Jozic, Vladislav Grigoriev, Gaurav Sahay, Daniel L. Marks. Comprehensive therapeutic impact: Follistatin mRNA-loaded lipid nanoparticles halt lung metastases and prolong survival in murine head & neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB019.