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  • Byrgazov, KonstantinOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.;St Anna Childrens Canc Res Inst CCRI, Vienna, Austria. (author)

Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2020-07-29
  • SAGE PUBLICATIONS LTD,2020
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-421048
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-421048URI
  • https://doi.org/10.1177/1758835920937891DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • 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 ofANPEPgene 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 HGOSex vivomodels and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigatedin vivo. Results: ElevatedANPEPexpression 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 HGOSex vivosamples 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 ofANPEP. In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effectsin 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.

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  • Andersson, ClaesUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)cland109 (author)
  • Salzer, BenjaminSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria. (author)
  • Bozsaky, EvaSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria. (author)
  • Larsson, RolfUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)rolflars (author)
  • Gullbo, JoachimOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden. (author)
  • Lehner, ManfredSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria. (author)
  • Lehmann, FredrikOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden. (author)
  • Slipicevic, AnaOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden. (author)
  • Kager, LeoMed Univ Vienna, St Anna Childrens Hosp, Dept Pediat, Vienna, Austria.;CCRI, Vienna, Austria. (author)
  • Fryknäs, MårtenUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)mafry516 (author)
  • Taschner-Mandl, SabineSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria. (author)
  • Oncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.;St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.Cancerfarmakologi och beräkningsmedicin (creator_code:org_t)

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  • In:THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY: SAGE PUBLICATIONS LTD121758-83401758-8359

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