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HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model
Thaiz F Borin1, Adarsh Shankar1, Kartik Angara1
1Georgia Cancer Center, Augusta University, Augusta, GA, United States of America.
Abstract:
Distant metastasis is the primary cause of death in the majority of the cancer types. Recently, much importance has been given to tumor microenvironment (TME) in the development of invasive malignant tumors, as well as the metastasis potential. The ability of tumor cells to modulate TME and to escape immune-mediated attack by releasing immunosuppressive cytokines has become a hallmark of breast cancer. Our study shows the effect of IV formulation of HET0016 (HPßCD-HET0016) a selective inhibitor of 20-HETE synthesis, administered intravenously in immune-competent in vivo mouse model of murine breast cancer. 4T1 luciferase positive cells were implanted to the mammary fat pad in Balb/c mice. Treatment started on day 15, and was administered for 5 days a week for 3 weeks. The development of metastasis was detected via optical imaging. Blood, spleen, lungs, bone marrow and tumor were collected for flow cytometry, to investigate changes in myeloid-derived suppressive cells (MDSCs) populations and endothelial phenotype. Tumor and lungs were collected for protein analysis. Our results show that HPßCD-HET0016: (1) decreased tumor volume and lung metastasis compared to the vehicle group; (2) reduced migration and invasion of tumor cells and levels of metalloproteinases in the lungs of animals treated with HPßCD-HET0016 via PI3K/AKT pathway; and (3) decreased expression of pro-inflammatory cytokines, growth factors and granulocytic MDSCs population in the lung microenvironment in treated animals. Thus, HPßCD-HET0016 showed potential in treating lung metastasis in a preclinical mouse model and needs further investigations on TME.
Insights
This study demonstrates that HPßCD-HET0016, a 20-HETE synthesis inhibitor, effectively reduces breast cancer lung metastasis in mice. The treatment also modulated the tumor microenvironment and immune cell populations, showing therapeutic potential.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Distant metastasis is a major cause of cancer mortality.
- The tumor microenvironment (TME) plays a critical role in cancer progression and metastasis.
- Breast cancer cells can evade immune surveillance by manipulating the TME and releasing immunosuppressive cytokines.
Purpose of the Study:
- To investigate the efficacy of intravenously administered HPßCD-HET0016, a selective 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis inhibitor, in a preclinical mouse model of breast cancer.
- To evaluate the impact of HPßCD-HET0016 on tumor growth, lung metastasis, and the tumor microenvironment.
Main Methods:
- A murine breast cancer model was established by implanting 4T1 luciferase-positive cells in Balb/c mice.
- Mice received intravenous HPßCD-HET0016 or vehicle control for 3 weeks.
- Metastasis was monitored using optical imaging. Flow cytometry and protein analysis were performed on collected tissues to assess immune cell populations, endothelial phenotype, and molecular markers.
Main Results:
- HPßCD-HET0016 significantly reduced tumor volume and lung metastasis compared to the vehicle group.
- Treatment with HPßCD-HET0016 decreased tumor cell migration and invasion, and lowered metalloproteinase levels in the lungs, potentially via the PI3K/AKT pathway.
- The drug also reduced pro-inflammatory cytokines, growth factors, and granulocytic myeloid-derived suppressive cells (MDSCs) in the lung microenvironment.
Conclusions:
- HPßCD-HET0016 demonstrates significant potential in inhibiting lung metastasis in a preclinical breast cancer model.
- The drug's efficacy appears linked to its ability to modulate the tumor microenvironment, including immune cell populations and signaling pathways.
- Further research is warranted to explore HPßCD-HET0016's therapeutic applications, particularly concerning its effects on the TME.
