Targeting Aggressive Osteosarcoma with a Peptidase-enhanced Cytotoxic Melphalan Flufenamide

Overview

Journal Ther Adv Med Oncol

Specialty Oncology

Date 2020 Aug 11

PMID 32774473

Citations 4

Authors

Konstantin Byrgazov

Claes Anderson

Benjamin Salzer

Eva Bozsaky

Rolf Larsson

Joachim Gullbo

Manfred Lehner

Fredrik Lehmann

Ana Slipicevic

Leo Kager

Marten Fryknas

Sabine Taschner-Mandl

Affiliations

Soon will be listed here.

Abstract

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 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 models and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigated .

Results: Elevated 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 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 . In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effects .

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.

Citing Articles

The Peptide-Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death.

Flanagan K, Kumari R, Miettinen J, Haney S, Varney M, Williams J Hemasphere. 2022; 6(3):e687.

PMID: 35243210 PMC: 8884539. DOI: 10.1097/HS9.0000000000000687.

2021 FDA TIDES (Peptides and Oligonucleotides) Harvest.

Al Shaer D, Al Musaimi O, Albericio F, de la Torre B Pharmaceuticals (Basel). 2022; 15(2).

PMID: 35215334 PMC: 8876803. DOI: 10.3390/ph15020222.

Spotlight on Melphalan Flufenamide: An Up-and-Coming Therapy for the Treatment of Myeloma.

Morabito F, Tripepi G, Martino E, Vigna E, Mendicino F, Morabito L Drug Des Devel Ther. 2021; 15:2969-2978.

PMID: 34262262 PMC: 8275138. DOI: 10.2147/DDDT.S295215.

Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells.

Byrgazov K, Besse A, Kraus M, Slipicevic A, Lehmann F, Driessen C Hemasphere. 2021; 5(7):e602.

PMID: 34136753 PMC: 8202573. DOI: 10.1097/HS9.0000000000000602.

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