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

被引：59

作者：

Chitty, Jessica L. ^{[1
,2
,3
]}

Yam, Michelle ^{[1
,2
,4
,5
]}

Perryman, Lara ^{[4
]}

Parker, Amelia L. ^{[1
,2
,3
]}

Skhinas, Joanna N. ^{[1
,2
]}

Setargew, Yordanos F. I. ^{[1
,2
]}

Mok, Ellie T. Y. ^{[1
,2
]}

Tran, Emmi ^{[1
,2
]}

Grant, Rhiannon D. ^{[1
,2
]}

Latham, Sharissa L. ^{[2
,3
,5
]}

Pereira, Brooke A. ^{[2
,3
,5
]}

Ritchie, Shona C. ^{[2
,5
]}

Murphy, Kendelle J. ^{[2
,3
,5
]}

Trpceski, Michael ^{[2
,3
,5
]}

Findlay, Alison D. ^{[4
]}

Melenec, Pauline ^{[2
,5
]}

Filipe, Elysse C. ^{[2
,3
]}

Nadalini, Audrey ^{[1
,2
]}

Velayuthar, Sipiththa ^{[1
,2
]}

Major, Gretel ^{[1
,2
]}

Wyllie, Kaitlin ^{[1
,2
]}

Papanicolaou, Michael ^{[1
,2
]}

Ratnaseelan, Shivanjali ^{[1
,2
]}

Phillips, Phoebe A. ^{[6
]}

Sharbeen, George ^{[6
]}

Youkhana, Janet ^{[6
]}

Russo, Alice ^{[2
,5
]}

Blackwell, Antonia ^{[2
,5
]}

Hastings, Jordan F. ^{[2
,5
]}

Lucas, Morghan C. ^{[2
,5
]}

Chambers, Cecilia R. ^{[2
,5
]}

Reed, Daniel A. ^{[2
,5
]}

Stoehr, Janett ^{[2
,5
]}

Vennin, Claire ^{[2
,5
]}

Pidsley, Ruth ^{[2
,3
,5
]}

Zaratzian, Anaiis ^{[2
,5
]}

Da Silva, Andrew M. ^{[2
,5
]}

Tayao, Michael ^{[2
,5
]}

Charlton, Brett ^{[4
]}

Herrmann, David ^{[1
,2
,3
]}

Nobis, Max ^{[2
,3
,5
,14
]}

Clark, Susan J. ^{[2
,3
,5
]}

Biankin, Andrew V. ^{[7
,8
]}

Johns, Amber L. ^{[2
,5
]}

Croucher, David R. ^{[2
,3
,5
]}

Nagrial, Adnan ^{[9
]}

Gill, Anthony J. ^{[2
,5
,10
,11
,12
]}

Grimmond, Sean M. ^{[13
]}

Pajic, Marina ^{[2
,3
,5
]}

Timpson, Paul ^{[1
,3
]}

机构：

[1] Garvan Inst Med Res, Canc Ecosyst Program, Darlinghurst, NSW, Australia

[2] Kinghorn Canc Ctr, Darlinghurst, NSW, Australia

[3] UNSW Sydney, Sch Clin Med, St Vincents Healthcare Clin Campus, UNSW Med & Hlth, Sydney, NSW, Australia

[4] Pharmaxis, Frenchs Forest, NSW, Australia

[5] Garvan Inst Med Res, Darlinghurst, NSW, Australia

[6] UNSW Sydney, Sch Biomed Sci, Lowy Canc Res Ctr, Fac Med, Sydney, NSW, Australia

[7] Univ Glasgow, Sch Canc Sci, Wolfson Wohl Canc Res Ctr, Glasgow, Scotland

[8] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow, Scotland

[9] Westmead Hosp, Dept Med Oncol, Sydney, NSW, Australia

[10] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia

[11] Royal North Shore Hosp, Dept Anat Pathol, NSW Hlth Pathol, Sydney, NSW, Australia

[12] Kolling Inst Med Res, Canc Diag & Pathol Res Grp, Sydney, NSW, Australia

[13] Univ Melbourne, VCCC, Ctr Canc Res, Melbourne, Vic, Australia

[14] VIB, Intravital Imaging Expertise Ctr, VIB Ctr Canc Biol, Leuven, Belgium

来源：

NATURE CANCER | 2023年 / 4卷 / 09期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

DUCTAL ADENOCARCINOMA; DOUBLE-BLIND; TISSUE SAMPLES; PHASE-II; FIBROSIS; METASTASIS; SIMTUZUMAB; PLACEBO; CHEMOTHERAPY; COMBINATION;

D O I：

10.1038/s43018-023-00614-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1326 / +

页数：32

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