Thomas R. Cox, Feb 2017
Our new paper on the pre-clinical testing of two novel potential anti-cancer drugs in breast cancer has just been published in Oncotarget.
In this paper we describe the generation and characterisation of two novel small molecule amine oxidase inhibitors against the lysyl oxidase family of proteins. The first drug targets the Lysyl Oxidase like 2 (LOXL2) enzyme alone; and a second dual inhibitor targets both the LOXL2 and Lysyl Oxidase (LOX) enzymes.
The lysyl oxidase family has garnered much attention over recent years. Consisting of Lysyl oxidase (LOX) and 4 LOX-like enzymes (LOXL1 to 4), this is a family of secreted, copper dependent amine oxidases, which predominantly catalyze the cross-linking of components of the extracellular matrix.
We profiled the anti-tumor properties of these inhibitors in a human breast cancer model, and using their specific selectivity profiles, confirm a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 enzymatic activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis and fibroblast activation. Dual inhibition of LOXL2 and LOX simultaneously showed more powerful effects and also led to a lower overall metastatic burden in the lung and liver.
This is the first report on the anti-tumour effects of selective LOX/LOXL2 small molecule inhibitors in models of human breast cancer and strongly supports the continued development of selective LOX and LOXL2 small molecule inhibitors for use in the treatment of human cancers.
Lysyl Oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases is known to be important in normal tissue development and homeostasis, as well as the onset and progression of solid tumors. Here we tested the anti-tumor properties of two generations of novel small molecule LOXL2 inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis. Dual inhibition of LOXL2 and LOX showed a greater effect and also led to a lower overall metastatic burden in the lung and liver. Our data provides the first evidence to support a role for LOXL2 specific small molecule inhibitors as a potential therapy in breast cancer.
Chang, J., Lucas, M., Leonte, L., Garcia-Montolio, M., Babloo Singh, L., Findlay, A., Deodhar, M., Foot, J., Jarolimek, W., Timpson, P., Erler, J., & Cox, TR. (2017).
Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer.
This research was supported by funding from the Biotech Research and Innovation Centre (BRIC) University of Copenhagen; a Hallas Møller Stipendum from the Novo Nordisk Foundation; The Danish Council for Strategic Research Innovation Fund; a National Health and Medical Research Council NHMRC New Investigator grant; a National Health and Medical Research Council NHMRC Project grant; Cancer Council NSW; Tour de Cure, and a Len Ainsworth Fellowship. We thank Pharmaxis for supply of the LOXL2 inhibitors. In addition, some experiments were performed with financial support provided by Pharmaxis.
Four of the authors on this paper (A.D. Findlay, M. Deodhar, J.S. Foot and W. Jarolimek) are employees of Pharmaxis Pharmaceutical Ltd., a company with ownership of PXS-S1A, PXS-S2A and PXS-S2B, which are the compounds described in the paper.