Publications

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.; 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.; Abdulkhalek, Lea; Schmitz, Tatjana; Lee, Victoria; Stewart, Kym Pham; Arshi, Mehreen; Steinmann, Angela M.; Pajic, Marina; Timpson, Paul; Jarolimek, Wolfgang; Cox, Thomas R.

Title:

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Year:

2023

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Referee:

No

Name of journal:

NATURE CANCER

ISSN of journal:

2662-1347

N° Volume:

4

Number or Folder:

9

Page numbers:

1326-1344

Keyword:

tumour target, xenograft, pancreatic cancer, lysl oxidase

Short description of contents:

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.Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.

Note:

Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s43018-023-00614-y

Product ID:

137769

Handle IRIS:

11562/1119448

Last Modified:

February 12, 2025

Bibliographic citation:

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.; 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.; Abdulkhalek, Lea; Schmitz, Tatjana; Lee, Victoria; Stewart, Kym Pham; Arshi, Mehreen; Steinmann, Angela M.; Pajic, Marina; Timpson, Paul; Jarolimek, Wolfgang; Cox, Thomas R., A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer «NATURE CANCER» , vol. 4 , n. 9 , 2023 , pp. 1326-1344

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo