Publication: Targeting LOX in Cancer

Thomas R. Cox, Jan 2016

Over the last 2 decades there has been a rapidly increasing number of research papers published (many from our own lab) investigating the function and role of a secreted enzyme called Lysyl Oxidase (LOX). Each paper has added successive small pieces to the complex puzzle of what exactly LOX does in both normal development and human disease, none less so than cancer.

LOX publications by year

The last decade has seen an explosion in the number of papers reporting on Lysyl Oxidase (LOX)

Work from our lab and many others has shown that the expression of LOX in solid tumours is incredibly important in determining not only the behaviour of tumours, but also the long-term outcome of patients. Furthermore, this importance is not limited to a single cancer type, and work has shown that LOX is critically important in many solid tumours including breast cancer, colorectal cancer, head & neck cancer, pancreatic cancer, lung cancer, prostate cancer and more… (for a more detailed discussion see our paper in Nature Reviews Cancer)

This explosion of interest in a protein (for which we still do not have a crystal structure) has led many researchers to propose LOX as a viable therapeutic target for cancer, and kicked off several large scale drug development programs.

Cox_Cancer_Research_Reviews_2016

The prometastatic effects of LOX secreted by hypoxic breast cancers. Tumor hypoxia drives the expression and secretion of LOX into the circulation (1), which travels to the bone (2) and acts to disrupt the osteoblast/osteoclast balance in favor of bone destruction, leading to the generation of focal premetastatic osteolytic lesions (3). These subsequently act to enhance metastatic colonization of circulating tumor cells. 4, treatment with anti- LOX antibodies or bisphosphonates abrogate premetastatic niche formation and reduce metastatic colonization.

In our recently published paper we review the concept of targeting LOX in the context of cancer and the likely success that different approaches may yield. We discuss the feasibility of  complete inhibition, modulating expression and activity, to reversing its action and finally blocking cellular response to LOX-mediated events. We conclude that whilst targeting LOX and its action will be a powerful tool in our arsenal for the treatment of solid cancers, further studies are currently needed to bring it to the clinic.

Abstract

Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no “cures” for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types.

Links

View abstract on PubMed
View article on Cancer Research homepage

Citation

Cox TR, Gartland A, Erler JT. Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis
Cancer Research (2016) | doi:10.1158/0008-5472.CAN-15-2306