Thomas R. Cox, Nov 2019
Targeting the lysyl oxidases in tumour desmoplasia
Our recent review discussing the importance, and also the therapeutic potential of inhibiting the lysyl oxidase (LOX) family of enzymes as a stromal targeting therapy has just been published in Biochemical Society Transactions.
In this review, we discuss the importance of the lysyl oxidases in the biogenesis of the extracellular matrix (ECM) and in particular during fibrosis and tumour desmoplasia. We outline the fundamental role that the lysyl oxidases play in the deposition of fibrillar collagens within solid tumours and how they offer a tractable therapeutic target as a stromal co-targetting approach. We finish by covering the various approaches and avenues that have been taken in order to develop inhibitors to this family, and the current status and potential that each offers.
The extracellular matrix (ECM) is a fundamental component of tissue microenvironments and its dysregulation has been implicated in a number of diseases, in particular cancer. Tumour desmoplasia (fibrosis) accompanies the progression of many solid cancers, and is also often induced as a result of many frontline chemotherapies. This has recently led to an increased interest in targeting the underlying processes. The major structural components of the ECM contributing to desmoplasia are the fibrillar collagens, whose key assembly mechanism is the enzymatic stabilisation of procollagen monomers by the lysyl oxidases. The lysyl oxidase family of copper-dependent amine oxidase enzymes are required for covalent cross-linking of collagen (as well as elastin) molecules into the mature ECM. This key step in the assembly of collagens is of particular interest in the cancer field since it is essential to the tumour desmoplastic response. LOX family members are dysregulated in many cancers and consequently the development of small molecule inhibitors targeting their enzymatic activity has been initiated by many groups. Development of specific small molecule inhibitors however has been hindered by the lack of crystal structures of the active sites, and therefore alternate indirect approaches to target LOX have also been explored. In this review, we introduce the importance of, and assembly steps of the ECM in the tumour desmoplastic response focussing on the role of the lysyl oxidases. We also discuss recent progress in targeting this family of enzymes as a potential therapeutic approach.
Chitty JL et al. Targeting the lysyl oxidases in tumour desmoplasia
Biochemical Society Transactions (2019) | doi: 10.1042/BST20190098
Cancer; Extracellular Matrix; Fibrosis; Lysyl Oxidases; Metastasis
J.L.C., Y.I.F.S and T.R.C. are supported by the NHMRC, Cancer Institute NSW (CINSW), Cancer Council NSW and Susan G. Komen.
The authors, J.L.C., Y.F.I.S. and T.R.C. are engaged in a collaborative project with Pharmaxis Ltd., a pharmaceutical company with ownership of a small molecule LOX family targeting pipeline including PXS-S1A, PXS-5120A (PXS-S2A), PXS-5129 (PXS-S2B), PXS-5153A, PXS-S1C and PXS-S3A mentioned in this review.