On August 29, 2023 y Pharmaxis Ltd (ASX: PXS) reported publication in the prestigious journal Nature Cancer of preclinical results showing pan‐Lysyl Oxidase (pan‐LOX) inhibitor PXS‐5505 increases survival by 35% compared to chemotherapy treatment alone in the treatment of pancreatic ductal adenocarcinomas (Press release, Pharmaxis, AUG 29, 2023, View Source;utm_campaign=PXS%20Cancer%20Drug%20Shows%20Increased%20Survival%20in%20Preclinical%20Models%20of%20Aggressive%20Pancreatic%20Cancer&utm_content=PXS%20Cancer%20Drug%20Shows%20Increased%20Survival%20in%20Preclinical%20Models%20of%20Aggressive%20Pancreatic%20Cancer+CID_c1c2ee092add41ee681fc9a7144e424a&utm_source=Campaign%20Monitor&utm_term=View%20Full%20Media%20Release [SID1234634721]).
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Research in mouse models, led by a team at the Garvan Institute of Medical Research in Sydney, Australia, also showed PXS‐5505 combined with chemotherapy reduced the spread of the cancer to other organs such as the liver by 45%. Pancreatic ductal adenocarcinoma is one of the most aggressive forms of pancreatic cancer with a five‐year survival rate of less than 10%.
Associate Professor Thomas Cox, head of the Matrix & Metastasis Lab at Garvan and senior author of the study, said, "The preclinical validation of this first‐in‐class anti‐fibrotic drug marks a major milestone in the quest to overcome the significant challenges in treating pancreatic cancer and brings hope to patients and their families."
Pharmaxis Chief Executive Gary Phillips said, "We have already seen very promising early results in a phase 2 trial with patients that have the bone marrow cancer myelofibrosis. This ground‐breaking research stems from a long collaboration with the team of high calibre researchers at the Garvan Institute and provides exciting new evidence that PXS‐5505 may also have a role as a therapy to improve the effect of current chemotherapy drugs in solid tumours like pancreatic cancer and extending the life of patients."
PXS‐5505 is an anti‐fibrotic pan‐Lysyl Oxidase (pan‐LOX) inhibitor that has completed long‐term toxicity studies and Phase 1a and 1b clinical trials demonstrating a well‐tolerated drug that effectively inhibits all enzymes in the lysyl oxidase family that are involved in fibrosis. Pancreatic cancer is often diagnosed at an advanced stage, which means that chemotherapy is usually the only treatment option available. Many pancreatic cancers develop chemotherapy resistance soon after treatment starts, which contributes to the poor survival of patients. Part of this resistance is driven by tumour fibrosis forming a mesh of scar tissue within and around pancreatic tumours that in turn reduces the effectiveness of chemotherapy drugs.
"PXS‐5505 returns the tumour microenvironment to a more "normal" state by reducing fibrosis and decreasing tumour stiffness," said Dr Jessica Chitty, Senior Research Officer at Garvan and first author of the study. "This allows chemotherapy drugs to penetrate the tumours more easily, work more effectively, and destroy more cancer cells.
The Nature Cancer publication can be seen here: View Source;023‐ 00614‐y. It adds to the body of pre‐clinical evidence published from other Pharmaxis collaborations with leading scientific institutions in the last year on the role of LOX enzymes in disease including:
Inhibition of lysyl oxidases synergizes with 5‐azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies; Nature Communications 2023 View Source;023‐37175‐8
Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis, Nature Communications 2022 View Source;022‐33148‐5
Pan‐Lysyl Oxidase Inhibitor PXS‐5505 Ameliorates Multiple‐Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis, International Journal of Molecular Sciences 2022 View Source