A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
Jessica L. Chitty(Garvan Institute of Medical Research), Michelle Yam(Garvan Institute of Medical Research), Lara Perryman(Pharmaxis (Australia)), Amelia L. Parker(Garvan Institute of Medical Research), Joanna N. Skhinas(Garvan Institute of Medical Research), Yordanos F. Setargew(Garvan Institute of Medical Research), Ellie T. Y. Mok(Garvan Institute of Medical Research), Emmi Tran(Garvan Institute of Medical Research), Rhiannon D. Grant(Garvan Institute of Medical Research), Sharissa L. Latham(Garvan Institute of Medical Research), Brooke Pereira(Garvan Institute of Medical Research), Shona Ritchie(Garvan Institute of Medical Research), Kendelle J. Murphy(Garvan Institute of Medical Research), Michael Trpceski(Garvan Institute of Medical Research), Alison D. Findlay(Pharmaxis (Australia)), Pauline Mélénec(Garvan Institute of Medical Research), Elysse C. Filipe(Garvan Institute of Medical Research), Audrey Nadalini(Garvan Institute of Medical Research), Sipiththa Velayuthar(Garvan Institute of Medical Research), Gretel Major(Garvan Institute of Medical Research), Kaitlin Wyllie(Garvan Institute of Medical Research), Michael Papanicolaou(Garvan Institute of Medical Research), Shivanjali Ratnaseelan(Garvan Institute of Medical Research), Phoebe A. Phillips(UNSW Sydney), George Sharbeen(UNSW Sydney), Janet Youkhana(UNSW Sydney), Alice Russo(Garvan Institute of Medical Research), Antonia Blackwell(Garvan Institute of Medical Research), Jordan F. Hastings(Garvan Institute of Medical Research), Morghan C. Lucas(Garvan Institute of Medical Research), Cecilia R. Chambers(Garvan Institute of Medical Research), Daniel A. Reed(Garvan Institute of Medical Research), Janett Stoehr(Garvan Institute of Medical Research), Claire Vennin(Garvan Institute of Medical Research), Ruth Pidsley(Garvan Institute of Medical Research), Anaiis Zaratzian(Garvan Institute of Medical Research), Andrew M. Da Silva(Garvan Institute of Medical Research), Michael Tayao(Garvan Institute of Medical Research), Brett Charlton(Pharmaxis (Australia)), David Herrmann(Garvan Institute of Medical Research), Max Nobis(Garvan Institute of Medical Research), Susan J. Clark(Garvan Institute of Medical Research), Andrew V. Biankin(Glasgow Royal Infirmary), Amber L. Johns(Garvan Institute of Medical Research), David R. Croucher(Garvan Institute of Medical Research), Adnan Nagrial(Westmead Hospital), Anthony J. Gill(The University of Sydney), Sean M. Grimmond(The University of Melbourne), Australian Pancreatic Cancer Genome Initiative (APGI)(Garvan Institute of Medical Research), Lorraine A. Chantrill(Garvan Institute of Medical Research), Angela Chou(Garvan Institute of Medical Research), Tanya Dwarte(Garvan Institute of Medical Research), Xanthe L. Metcalf(Garvan Institute of Medical Research), Gloria Jeong(Garvan Institute of Medical Research), Lara Kenyon(Garvan Institute of Medical Research), Nicola Waddell(QIMR Berghofer Medical Research Institute), John V. Pearson(QIMR Berghofer Medical Research Institute), Ann-Marie Patch(QIMR Berghofer Medical Research Institute), Kátia Nones(QIMR Berghofer Medical Research Institute), Felicity Newell(QIMR Berghofer Medical Research Institute), Pamela Mukhopadhyay(QIMR Berghofer Medical Research Institute), Venkateswar Addala(QIMR Berghofer Medical Research Institute), Stephen H. Kazakoff(QIMR Berghofer Medical Research Institute), Oliver Holmes(QIMR Berghofer Medical Research Institute), Conrad Leonard(QIMR Berghofer Medical Research Institute), Scott Wood(The University of Melbourne), Oliver Hofmann(The University of Melbourne), Jaswinder S. Samra(Royal North Shore Hospital), Nick Pavlakis(Royal North Shore Hospital), Jennifer Arena(Royal North Shore Hospital), Hilda A. High(Royal North Shore Hospital), Ray Asghari(Bankstown Lidcombe Hospital), Neil D. Merrett(Bankstown Lidcombe Hospital), Amitabha Das(Bankstown Lidcombe Hospital), Peter H. Cosman(Liverpool Hospital), Kasim Ismail(Liverpool Hospital), Alina Stoita(St Vincent's Hospital Sydney), David Williams(St Vincent's Hospital Sydney), Allan Spigellman(Westmead Hospital), Duncan McLeo(Westmead Hospital), Judy Kirk(Royal Prince Alfred Hospital), James G. Kench(Royal Prince Alfred Hospital), Peter Grimison(Royal Prince Alfred Hospital), Charbel Sandroussi(Royal Prince Alfred Hospital), Annabel Goodwin(Garvan Institute of Medical Research), R. Scott Mead(Garvan Institute of Medical Research), Katherine L. Tucker(Prince of Wales Hospital), Lesley Andrews(Fremantle Hospital), Michael Texler(Fremantle Hospital), Cindy Forrest(Fremantle Hospital), Mo Ballal(St John of God Subiaco Hospital), David Fletcher(St John of God Subiaco Hospital), Maria Beilin(St John of God Subiaco Hospital), Kynan Feeney(St John of God Subiaco Hospital), Krishna Epari(St John of God Subiaco Hospital), Sanjay Mukhedkar(St John of God Subiaco Hospital), Nikolajs Zeps(Royal Adelaide Hospital), Nan Q. Nguyen(Royal Adelaide Hospital), Andrew Ruszkiewicz(Royal Adelaide Hospital), Chris Worthley(Royal Adelaide Hospital), John Chen(Flinders Medical Centre), Mark E. Brooke‐Smith(Flinders Medical Centre), Virginia Papangelis(Flinders Medical Centre), Andrew D. Clouston(Princess Alexandra Hospital), Andrew P. Barbour(Princess Alexandra Hospital), Thomas J. O’Rourke(Princess Alexandra Hospital), Jonathan W. Fawcett(Princess Alexandra Hospital), Kellee Slater(Princess Alexandra Hospital), Michael Hatzifotis(Princess Alexandra Hospital), Peter Hodgkinson(Austin Hospital), Mehrdad Nikfarjam(Austin Hospital), James R. Eshleman, Ralph H. Hruban, Christopher L. Wolfgang(University of Verona), Aldo Scarpa(University of Verona), Rita T. Lawlor(University of Verona), Vincenzo Corbo(University of Verona), Claudio Bassi(University of Verona), Nigel B. Jamieson(University of Glasgow), David K. Chang(Garvan Institute of Medical Research), Stephan B. Dreyer(Garvan Institute of Medical Research), Australian Pancreatic Cancer Matrix Atlas (APMA)(Garvan Institute of Medical Research), Lea Abdulkhalek(Garvan Institute of Medical Research), Tatjana Schmitz(Garvan Institute of Medical Research), Victoria Lee(Garvan Institute of Medical Research), Kym Pham Stewart(Garvan Institute of Medical Research), Mehreen Arshi(Garvan Institute of Medical Research), Angela Steinmann(Garvan Institute of Medical Research), Marina Pajic(Garvan Institute of Medical Research), Paul Timpson(Garvan Institute of Medical Research), Wolfgang Jarolimek(Pharmaxis (Australia)), Thomas R. Cox(Garvan Institute of Medical Research)
Cited by 122Open Access
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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