A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
Authors: 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. ,   Australian Pancreatic Cancer Genome Initiative (APGI), Chantrill Lorraine A. , Chou Angela , Dwarte Tanya , Metcalf Xanthe L. , Jeong Gloria , Kenyon Lara , Waddell Nicola , Pearson John V. , Patch Ann-Marie , Nones Katia , Newell Felicity , Mukhopadhyay Pamela , Addala Venkateswar , Kazakoff Stephen , Holmes Oliver , Leonard Conrad , Wood Scott , Hofmann Oliver , Samra Jaswinder S. , Pavlakis Nick , Arena Jennifer , High Hilda A. , Asghari Ray , Merrett Neil D. , Das Amitabha , Cosman Peter H. , Ismail Kasim , Stoita Alina , Williams David , Spigellman Allan , McLeo Duncan , Kirk Judy , Kench James G. , Grimison Peter , Sandroussi Charbel , Goodwin Annabel , Mead R. Scott , Tucker Katherine , Andrews Lesley , Texler Michael , Forrest Cindy , Ballal Mo , Fletcher David , Beilin Maria , Feeney Kynan , Epari Krishna , Mukhedkar Sanjay , Zeps Nikolajs , Nguyen Nan Q. , Ruszkiewicz Andrew R. , Worthley Chris , Chen John , Brooke-Smith Mark E. , Papangelis Virginia , Clouston Andrew D. , Barbour Andrew P. , O’Rourke Thomas J. , Fawcett Jonathan W. , Slater Kellee , Hatzifotis Michael , Hodgkinson Peter , Nikfarjam Mehrdad , Eshleman James R. , Hruban Ralph H. , Wolfgang Christopher L. , Scarpa Aldo , Lawlor Rita T. , Corbo Vincenzo , Bassi Claudio , Jamieson Nigel B. , Chang David K. , Dreyer Stephan B. ,   Australian Pancreatic Cancer Matrix Atlas (APMA), Abdulkhalek Lea , Schmitz Tatjana , Lee Victoria , Stewart Kym Pham , Arshi Mehreen , Steinmann Angela M. , Pajic Marina , Timpson Paul , Jarolimek Wolfgang , Cox Thomas R. 
Published: August 2023

AbstractThe 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.