Oral Presentation 36th Lorne Cancer Conference 2024

A novel first-in-class anti-fibrotic blunts tumour desmoplasia, rewires stromal signalling and augments gemcitabine response and survival in pancreatic cancer (#3)

Thomas R. Cox 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumour desmoplasia.

Using small-molecule drug-design approaches, we generated and validated PXS- 5505, a first-in-class highly selective, potent, mechanistic pan-lysyl oxidase inhibitor.

We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating anti-fibrotic effects in human patient-derived xenograft models of pancreatic cancer. Mechanistically, the decreases in tumour stiffness brought about by PXS-5505 reduces CAF activation within the tumour microenvironment and decreases STAT3 signalling in cancer cells to augment chemotherapy efficacy and prolong survival.

PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues, and has cleared Phase I safety trials thereby enabling Phase II trials. 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 (1).

  1. (1) Chitty JL et al. Nature Cancer (2023)