Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
Nat Cancer. 2023 Sep;4(9):1326-1344. doi: 10.1038/s43018-023-00614-y. Epub 2023 Aug 28.
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.
赖氨酰氧化酶家族在基质靶向治疗实体瘤中具有很大的应用潜力，因为该家族在交联和稳定纤维胶原方面具有重要作用，并且已知其在肿瘤纤维增生中发挥作用。我们采用小分子药物设计方法，生成并验证了 PXS-5505，这是一种首创的、高度选择性和有效的泛赖氨酰氧化酶抑制剂。我们在体外和体内证明，泛赖氨酰氧化酶抑制可减少化疗诱导的胰腺肿瘤纤维增生和硬度，降低癌细胞侵袭和转移，改善肿瘤灌注，并增强同源遗传工程 KPC 模型中化疗的疗效，同时在胰腺癌的人源异种移植模型中也表现出抗纤维化作用。PXS-5505 具有口服生物利用度，可安全有效地抑制组织中的赖氨酰氧化酶活性。我们的研究结果为进展中的泛赖氨酰氧化酶抑制剂提供了理论依据，旨在减少基质以增强胰腺导管腺癌的化疗效果。
