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

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.

Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to β-amyloid deposition and lysyl oxidase

“…We hypothesized LOX activity may account for the increased vessel stiffness we observed in arterioles with CAA. A recent study using pan-lysyl oxidase inhibition in pancreatic cancer showed remodeling and crosslinking with fibrillar collagen matrices, reducing the tumor stiffness [14].…”

Pyrvinium Pamoate Enhances the Anti-cancer Activities of Gemcitabine in Pancreatic Cancer

“…Pancreatic cancer, commonly referred to as PDAC, is a fatal disease with an incredibly poor prognosis and a 5-year survival rate of less than 10% [32]. Drug repurposing has shown great promise in the rapid identification of effective anti-PDAC drugs and several FDA-approved non-cancer drugs are currently being explored for the treatment of this lethal neoplasm [8].…”

Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

“…Due to strong evidence for dysregulated ECM crosslinking in promoting fibrosis and the key roles of ECM crosslinking enzymes, therapeutics are actively being investigated to target TG, LOX, and LH proteins, with the most advanced drug molecules in phase I/II clinical trials ( Table 1 ) [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. LOX therapeutics vary based on which LOX they target, and both small-molecule and antibody-based targeting approaches have been employed.…”