2023-08-30 ニューサウスウェールズ大学(UNSW)
◆膵臓がんは診断が進行段階で行われるため、化学療法が主な治療方法となるが、耐性が早期に現れることが多く、効果が低下する。新薬は線維組織のコラーゲン沈着を阻害し、膵臓腫瘍内の効果的な薬物浸透を促進する。
<関連情報>
- https://newsroom.unsw.edu.au/news/health/drug-targets-scar-tissue-tumours-shows-promise-pancreatic-cancer
- https://www.nature.com/articles/s43018-023-00614-y
ファーストインクラスの汎リシルオキシダーゼ阻害薬が間質リモデリングを障害し、膵癌におけるゲムシタビン奏効と生存を増強する 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. I. Setargew,Ellie T. Y. Mok,Emmi Tran,Rhiannon D. Grant,Sharissa L. Latham,Brooke A. Pereira,Shona C. Ritchie,Kendelle J. Murphy,Michael Trpceski,Alison D. Findlay,Pauline Melenec,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),Australian Pancreatic Cancer Matrix Atlas (APMA),Marina Pajic,Paul Timpson,Wolfgang Jarolimek & Thomas R. Cox
Nature Cancer Published:28 August 2023
DOI:https://doi.org/10.1038/s43018-023-00614-y
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.
