Abstract 4214
Background
High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor. In metastatic patients, survival rates are poor and remained virtually unchanged over the past 30 years. Furthermore, recent randomized trials failed to improve the efficacy of current chemotherapy. Here we tested the anti-neoplastic activity of a novel peptide-conjugated alkylator melflufen in preclinical osteosarcoma setting. Due to its high lipophilicity melflufen rapidly enters tumor cells where it is immediately cleaved by peptidases leading to entrapment and enrichment of alkylating payload. Overexpression of peptidases is often seen in tumor cells and can thus lead to increased melfufen sensitivity. In osteosarcoma, over-expression of aminopeptidase N (ANPEP/CD13) has been associated with poor survival and metastasis suggesting that melflufen may represent a valid new therapeutic option.
Methods
Gene expression of ANPEP/CD13 in patient samples from GEO datasets was analyzed using standard tools. Anti-neoplastic activity of melflufen and was evaluated in a panel of 11 osteosarcoma cell lines including early passage patient-derived primary lines. In vitro anti-neoplastic activity was examined using survival and apoptosis assays. In vivo activity of melflufen was tested in a chicken embryo xenograft model.
Results
Melflufen has demonstrated superior anti-neoplastic activity in comparison to other alkylating agents including melphalan, cyclophosphamide, ifosfamide, busulfan, and bendamustine. Melflufen was active in all osteosarcoma cell lines including the cells resistant to methotrexate, etoposide, and talazoparib. Anti-neoplastic activity of melflufen could be hindered by ANPEP inhibitor bestatin. Furthermore, in vivo administration of melflufen reduced tumor growth and metastasis of highly aggressive 143B osteosarcoma cells in a xenograft model.
Conclusions
Melflufen has demonstrated promising results in preclinical osteosarcoma model showing anti-neoplastic activity superior to other alkylating agents and PARP inhibitor talazoparib. Melflufen’s favorable toxicity profile suggests that it might represent a novel valid therapeutic approach for osteosarcoma patients with poor response to chemotherapy and metastasis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Oncopeptides AB.
Disclosure
A. Slipicevic: Full / Part-time employment: Oncopeptides AB. K. Byrgazov: Research grant / Funding (self): Oncopeptides AB. F. Lehmann: Full / Part-time employment: Oncopeptides AB; Leadership role: EpiEndo Pharmaceuticals. T. Lion: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Incyte. All other authors have declared no conflicts of interest.
Resources from the same session
1735 - mTOR inhibition in the treatment of resistant breast cancer
Presenter: María Rodriguez
Session: Poster Display session 1
Resources:
Abstract
6068 - Study of Photodynamic therapy in vitro
Presenter: Irene Jiménez Munguía
Session: Poster Display session 1
Resources:
Abstract
3011 - The potential of neratinib plus dasatinib in overcoming and preventing neratinib resistance in HER2-positive breast cancer models
Presenter: Neil Conlon
Session: Poster Display session 1
Resources:
Abstract
2644 - Novel HDACi, MHY446, induces apoptosis via regulation of mitochondria-endoplasmic reticulum interaction in HCT116 human colorectal cancer cells
Presenter: Nam Deuk Kim
Session: Poster Display session 1
Resources:
Abstract
3085 - Dual inhibition of TGF-β and AXL as a novel treatment for colorectal cancer
Presenter: Davide Ciardiello
Session: Poster Display session 1
Resources:
Abstract
1314 - PARP inhibition enhances cisplatin sensitivity in cervical cancer by modulating β-catenin signaling
Presenter: Minakshi Mann
Session: Poster Display session 1
Resources:
Abstract
2417 - Synergistic effect of DSF combined treatment with cisplatin in atypical teratoid/rhabdoid tumors (AT/RT)
Presenter: Seung Ah Choi
Session: Poster Display session 1
Resources:
Abstract
1149 - Reactive oxygen species induced by OSU-A9 inhibit the growth of duodenal cancer and gastric cancer cells through dephosphorylating intranuclear pyruvate kinase muscle isozyme M2
Presenter: Li-Yuan Bai
Session: Poster Display session 1
Resources:
Abstract
1862 - New therapy for intrahepatic cholangiocarcinoma targeted to cancer associated fibroblasts
Presenter: Takahiro Yamanaka
Session: Poster Display session 1
Resources:
Abstract
782 - Macrophage-cancer cell fusion is mediated by Phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation
Presenter: Ivan Shabo
Session: Poster Display session 1
Resources:
Abstract