Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide
| Autor: | Konstantin Byrgazov, Claes Anderson, Benjamin Salzer, Eva Bozsaky, Rolf Larsson, Joachim Gullbo, Manfred Lehner, Fredrik Lehmann, Ana Slipicevic, Leo Kager, Mårten Fryknäs, Sabine Taschner-Mandl |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Therapeutic Advances in Medical Oncology, Vol 12 (2020) |
| Druh dokumentu: | article |
| ISSN: | 1758-8359 17588359 |
| DOI: | 10.1177/1758835920937891 |
| Popis: | Background: Low survival rates in metastatic high-grade osteosarcoma (HGOS) have remained stagnant for the last three decades. This study aims to investigate the role of aminopeptidase N (ANPEP) in HGOS progression and its targeting with a novel lipophilic peptidase-enhanced cytotoxic compound melphalan flufenamide (melflufen) in HGOS. Methods: Meta-analysis of publicly available gene expression datasets was performed to determine the impact of ANPEP gene expression on metastasis-free survival of HGOS patients. The efficacy of standard-of-care anti-neoplastic drugs and a lipophilic peptidase-enhanced cytotoxic conjugate melflufen was investigated in patient-derived HGOS ex vivo models and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigated in vivo . Results: Elevated ANPEP expression in diagnostic biopsies of HGOS patients was found to significantly reduce metastasis-free survival. In drug sensitivity assays, melflufen has shown an anti-proliferative effect in HGOS ex vivo samples and cell lines, including those resistant to methotrexate, etoposide, doxorubicin, and PARP inhibitors. Further, HGOS cells treated with melflufen displayed a rapid induction of apoptosis and this sensitivity correlated with high expression of ANPEP . In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effects in vivo . Conclusion: This study may pave the way for use of melflufen as an adjuvant to doxorubicin in improving the therapeutic efficacy for the treatment of metastatic HGOS. |
| Databáze: | Directory of Open Access Journals |
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