A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
Jessica L. Chitty, Michelle Yam, Lara Perryman, Amelia L. Parker, Joanna N. Skhinas, Yordanos F. Setargew, Ellie T. Y. Mok, Emmi Tran, Rhiannon D. Grant, Sharissa L. Latham, Brooke Pereira, Shona Ritchie, Kendelle J. Murphy, Michael Trpceski, Alison D. Findlay, Pauline Mélénec, Elysse C. Filipe, Audrey Nadalini, Sipiththa Velayuthar, Gretel Major, Kaitlin Wyllie, Michael Papanicolaou, Shivanjali Ratnaseelan, Phoebe A. Phillips, George Sharbeen, Janet Youkhana, Alice Russo, Antonia Blackwell, Jordan F. Hastings, Morghan C. Lucas, Cecilia R. Chambers, Daniel A. Reed, Janett Stoehr, Claire Vennin, Ruth Pidsley, Anaiis Zaratzian, Andrew M. Da Silva, Michael Tayao, Brett Charlton, David Herrmann, Max Nobis, Susan J. Clark, Andrew V. Biankin, Amber L. Johns, David R. Croucher, Adnan Nagrial, Anthony J. Gill, Sean M. Grimmond, Australian Pancreatic Cancer Genome Initiative (APGI), Lorraine A. Chantrill, Angela Chou, Tanya Dwarte, Xanthe L. Metcalf, Gloria Jeong, Lara Kenyon, Nicola Waddell, John V. Pearson, Ann-Marie Patch, Kátia Nones, Felicity Newell, Pamela Mukhopadhyay, Venkateswar Addala, Stephen H. Kazakoff, Oliver Holmes, Conrad Leonard, Scott Wood, Oliver Hofmann, Jaswinder S. Samra, Nick Pavlakis, Jennifer Arena, Hilda A. High, Ray Asghari, Neil D. Merrett, Amitabha Das, Peter H. Cosman, Kasim Ismail, Alina Stoita, David Williams, Allan Spigellman, Duncan McLeo, Judy Kirk, James G. Kench, Peter Grimison, Charbel Sandroussi, Annabel Goodwin, R. Scott Mead, Katherine L. Tucker, Lesley Andrews, Michael Texler, Cindy Forrest, Mo Ballal, David Fletcher, Maria Beilin, Kynan Feeney, Krishna Epari, Sanjay Mukhedkar, Nikolajs Zeps, Nan Q. Nguyen, Andrew Ruszkiewicz, Chris Worthley
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.