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A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer.
Chitty, Jessica L; Yam, Michelle; Perryman, Lara; Parker, Amelia L; Skhinas, Joanna N; Setargew, Yordanos F I; Mok, Ellie T Y; Tran, Emmi; Grant, Rhiannon D; Latham, Sharissa L; Pereira, Brooke A; Ritchie, Shona C; Murphy, Kendelle J; Trpceski, Michael; Findlay, Alison D; Melenec, Pauline; Filipe, Elysse C; Nadalini, Audrey; Velayuthar, Sipiththa; Major, Gretel; Wyllie, Kaitlin; Papanicolaou, Michael; Ratnaseelan, Shivanjali; Phillips, Phoebe A; Sharbeen, George; Youkhana, Janet; Russo, Alice; Blackwell, Antonia; Hastings, Jordan F; Lucas, Morghan C; Chambers, Cecilia R; Reed, Daniel A; Stoehr, Janett; Vennin, Claire; Pidsley, Ruth; Zaratzian, Anaiis; Da Silva, Andrew M; Tayao, Michael; Charlton, Brett; Herrmann, David; Nobis, Max; Clark, Susan J; Biankin, Andrew V; Johns, Amber L; Croucher, David R; Nagrial, Adnan; Gill, Anthony J; Grimmond, Sean M; Pajic, Marina; Timpson, Paul.
Afiliação
  • Chitty JL; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Yam M; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Perryman L; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Parker AL; Pharmaxis, Frenchs Forest, New South Wales, Australia.
  • Skhinas JN; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Setargew YFI; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Mok ETY; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Tran E; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Grant RD; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Latham SL; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Pereira BA; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Ritchie SC; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Murphy KJ; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Trpceski M; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Findlay AD; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Melenec P; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Filipe EC; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Nadalini A; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Velayuthar S; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Major G; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Wyllie K; Pharmaxis, Frenchs Forest, New South Wales, Australia.
  • Papanicolaou M; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Ratnaseelan S; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Phillips PA; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Sharbeen G; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Youkhana J; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Russo A; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Blackwell A; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Hastings JF; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Lucas MC; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Chambers CR; School of Biomedical Sciences, Faculty of Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, New South Wales, Australia.
  • Reed DA; School of Biomedical Sciences, Faculty of Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, New South Wales, Australia.
  • Stoehr J; School of Biomedical Sciences, Faculty of Medicine, Lowy Cancer Research Centre, UNSW Sydney, Sydney, New South Wales, Australia.
  • Vennin C; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Pidsley R; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Zaratzian A; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Da Silva AM; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Tayao M; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Charlton B; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Herrmann D; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Nobis M; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Clark SJ; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
  • Biankin AV; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Johns AL; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Croucher DR; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Nagrial A; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Gill AJ; Pharmaxis, Frenchs Forest, New South Wales, Australia.
  • Grimmond SM; Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Pajic M; The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • Timpson P; Intravital Imaging Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
Nat Cancer ; 4(9): 1326-1344, 2023 09.
Article em En | MEDLINE | ID: mdl-37640930
ABSTRACT
The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pancreatopatias / Neoplasias Pancreáticas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Nat Cancer Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pancreatopatias / Neoplasias Pancreáticas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Nat Cancer Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália