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A caspase-6 and anti-HER2 antibody chimeric tumor-targeted proapoptotic molecule decreased metastasis of human
Li-Feng Wang1, Yong Zhou, Yan-Ming Xu
1State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
Abstract:
Human growth factor receptor-2 (HER2), overexpressed as a result of gene amplification, is detected in 20-40% of patients with breast, ovarian, endometrial, gastric, bladder, prostate, or lung cancers, correlated to metastasis of many tumors, and considered to be a poor prognostic indicator for these tumors. However, the data was controversial for HER2 overexpression and the prognosis of osteosarcoma, which is the most common primary malignant bone tumor, presents a therapeutic challenge in medical oncology due to its metastasis and poor response to current treatments. Previously, we reported that the immunocasp-6 gene fused by a HER2-specific single-chain antibody with domain II of Pseudomonas exotoxin A (PEA) and the 5' end of the truncated active caspase-6 could selectively suppress the HER2-positive tumor growth. In this study, we extend its application. We first confirmed the higher HER2 expression on the surface of metastatic osteosarcoma SOSP-9607(E10) cells, which then be proved specifically addicted to immunocasp-6-induced cells killing in vitro. Thereafter, the efficacy of immunocasp-6 was tested in an osteosarcoma lung metastasis mouse model using intramuscular (i.m.) injections of liposome-encapsulated vectors. Our results showed that the expression of the immunocasp-6 gene not only significantly prolonged animal's survival, but also greatly inhibited tumor metastasis. Thereby, our strategy suggests an alternative approach to treating HER2/neu-positive osteosarcoma.
Insights
This study shows that immunocasp-6 effectively targets Human Epidermal growth factor Receptor 2 (HER2)-positive osteosarcoma cells. This novel gene therapy significantly inhibits tumor metastasis and improves survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Human Epidermal growth factor Receptor 2 (HER2) overexpression is linked to poor prognosis in various cancers.
- HER2's role in osteosarcoma prognosis is debated, and this bone tumor presents treatment challenges due to metastasis and poor response to therapies.
- Previous work demonstrated immunocasp-6's ability to suppress HER2-positive tumor growth.
Purpose of the Study:
- To investigate the efficacy of immunocasp-6 in treating HER2-positive osteosarcoma.
- To confirm HER2 expression in metastatic osteosarcoma cells and assess immunocasp-6's selective killing ability.
- To evaluate immunocasp-6's therapeutic potential in a preclinical osteosarcoma lung metastasis model.
Main Methods:
- Confirmation of high HER2 expression on metastatic osteosarcoma SOSP-9607(E10) cells.
- In vitro assessment of immunocasp-6-induced cell killing.
- In vivo testing of liposome-encapsulated immunocasp-6 gene vectors in an osteosarcoma lung metastasis mouse model via intramuscular injection.
Main Results:
- Immunocasp-6 demonstrated specific killing of HER2-positive osteosarcoma cells in vitro.
- In vivo studies showed that immunocasp-6 gene expression significantly prolonged survival in tumor-bearing mice.
- Treatment with immunocasp-6 greatly inhibited lung metastasis in the osteosarcoma mouse model.
Conclusions:
- Immunocasp-6 is effective in targeting and suppressing HER2-positive osteosarcoma growth and metastasis.
- This gene therapy strategy offers a promising alternative treatment approach for HER2/neu-positive osteosarcoma.
- The findings support further development of immunocasp-6 for clinical application in treating this challenging bone cancer.
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