|Michele Madigan||BOptom PhD, Basic Science, UNSW and Usyd|
|R Max Conway||PhD FRANZCO, Clinical and translational research|
|Svetlana Cherepanoff||PhD, MBBS, Anatomical Pathology, SEALS, Prince of Wales Hospital|
|Luis Munoz-Erazo||BSc, MSc, Research Assistant|
|Yong Li||PhD, Research Affiliate SSI, St George Hospital, UNSW|
We are studying ocular melanoma (affecting choroid, ciliary body, iris and conjunctiva). the most common primary intraocular eye cancer in adults. Our studies are investigating some of the mechanisms controlling cell proliferation, cell death and tumour invasion and angiogenesis, in order to better understand the pathogenesis of these tumours.
Combined clinical and laboratory research provides an understanding of the biology of these tumours and may improve the rationale for treatment. This is especially important given the morbidity associated with enucleation, the side effects of current therapies, particularly radiation and chemotherapy, and the high incidence of untreatable metastases that are characteristic of ocular melanoma.
Effects of histone deacetylase inhibitors (biological response modifiers) on growth and viability of ocular melanomas
Conway, Munoz-Erazos, Cherepanoff, Madigan
These studies are investigating the efficacy of various biologic response modifiers such as histone deacetylase inhibitors, curcumin and interferons in controlling intraocular, ocular surface and metastatic melanoma growth. These agents are very low in toxicity compared to chemotherapy drugs and can control tumour growth by inducing tumour cell differentiation and inhibiting cell division. Importantly, these agents do not seem to affect normal neighbouring cells in the eye, such as fibroblasts, epithelium and melanocytes. When combined with chemotherapy or radiation, some of these agents may potentially reduce the dose of chemotherapeutic agents or radiation required when treating tumours.
Matrix metalloproteinases (MMPs) and MMPInducing proteins in ocular melanoma
Madigan, Crouch (SEALS Anatomical Pathology, Prince of Wales Hospital), Jager (Leiden Medical Centre), Conway
Matrix metalloproteinases (MMPs) are a family of enzymes involved in degradation of extracellular matrix components such as collagen, laminin and proteoglycans. MMPs are involved in normal development, wound healing, new blood vessel growth and tumour invasion and metastases. Tissue inhibitors of MMPs (TIMPs) can block the activity of MMPs but are also important in cell death and angiogenesis. Our studies in ocular melanoma indicate involvement of MMP-1, -2, -9 and MT1-MMP and TIMP-2 and -3 in tumour angiogenesis and progression. MMP-8 is also found to be expressed in conjunctival melanoma and we are currently investigating its functional significance; MMP-8 is often mutated in cutaneous melanoma In vitro studies support these findings, where co-cultures of fibroblasts and melanoma cells display enhanced MMP-2 activity compared to fibroblasts or melanoma cells alone. The expression patterns of MMPs and TIMPs in detached retina overlying ocular melanomas also suggests an important role for MMPs in retinal gliosis and in neurite remodelling during retinal detachment.
Hyaluronan receptors (CD44s) and EMMPRIN in ocular melanoma
Madigan, Conway and Li (UNSW)
CD44 are a group of cell membrane proteins that are involved in cell-cell and cell-matrix adhesion and have been implicated in tumour cell-extracellular matrix (ECM) adhesion and metastatic spread in various malignancies including cutaneous melanoma. CD44s is a receptor for several ECM proteins including laminin and hyaluronan; hyaluronan is critical for tumour invasion and its production is also upregulated by CD147 (EMMPRIN). CD147 can modify the tumour microenvironment by activating proteinases, inducing angiogenic factors and interacting with monocarboxylate transporters (MCTs). We have found CD44s and CD147 expression in primary choroidal, iris and conjunctival melanomas.
Ocular melanoma and Cancer Testis (CT) Antigens
Errington (UNSW), , Cebon (Ludwig Institute, Uni. Melbourne), Madigan, Conway
Metastatic disease in ocular melanoma remains untreatable, associated with late detection and resistance to conventional systemic therapies. Skin melanoma and many other tumours express specific cancer-testis (CT) antigens and vaccines that target these antigens can induce T-cell-mediated and humoral immune responses. We are studying primary uveal and conjunctival melanomas for expression of CT antigens, including MAGe antigens, and PRAME, to further assess their potential as targets for ocular melanoma immunotherapy. To date we find that ocular melanomas are distinct from other tumours, including cutaneous melanomas, with low or no expression of the MAGE-family CT antigens. Other CT antigen family members such PRAME may however be more promising as targets.
Development of an artificial eye
Conway, Ben-Nissan (UTS)
The consequence of some ocular diseases, especially tumours, may be the loss of an eye with significant functional and psychological sequelae. Hydroxyapatite is currently used to replace eyes lost due to any cause, however it may be associated with problems including the potential for extrusion, infection, reduced motility and loss of cosmesis over time. The group has developed a novel porous bioceramic with improved biointegration and mechanical properties, which promises better function and cosmesis over existing implants. The results of the physical studies have recently been published; in vivo evaluation is in progress.