The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.
Chitty, J.L. et al. Nat. Cancer 4, pages 1326–1344 (2023).
doi: doi.org/10.1038/s43018-023-00614-y.
Summary of the findings
Summary of the findingsChemotherapy is the standard-of-care for pancreatic cancer patients, but over time it becomes ineffective due to a tumour scarring response (desmoplasia) elicited by the treatment. This desmoplasia is rich in fibrillar collagens, and acts to reinforce oncogenic signalling, accelerate progression, and protect the tumour from further rounds of treatment. It is thought that tumour desmoplasia contributes significantly to the poor survival rates of pancreatic cancer patients.
Lysyl oxidases catalyse crosslinking of collagen and are fundamental to the deposition and stabilisation of fibrillar collagens. In several solid cancers, lysyl oxidases are prognostic biomarkers since they are upregulated during tumour progression and further elevated during therapy-induced tumour desmoplasia. As such, targeting them is a promising avenue of research that has yet to be deployed in the clinic.
This work presents the development and validation of a novel, first-in-class mechanism-based pan-lysyl oxidase inhibitor (PXS-5505). It demonstrates that PXS-5505 functions as a bona fide anti-fibrotic agent to decrease chemotherapy-induced tumour desmoplasia and potentiate the efficacy of chemotherapy in pancreatic cancer to improve survival.
Future impact
The poor survival rates facing pancreatic cancer patients mean that novel treatment avenues are needed. Anti-stromal therapies that co-target tumour desmoplasia offer a significant translational impact for enhancing already approved therapy efficacy and improving patient outcome. PXS-5505 is an orally bioavailable, well tolerated, safe and effective mechanistic inhibitor of lysyl oxidase activity, which is currently in Phase 2 studies for haematological malignancies. Our findings present the rationale for including a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in therapy-induced tumour desmoplasia to potentiate efficacy of chemotherapy in the treatment of pancreatic ductal adenocarcinoma patients.
