Antitumour treatmentTargeted therapy for uveal melanoma
Introduction
The eye’s uveal tract comprises the iris, ciliary body, and choroid. It contains a population of melanocytes from which develops uveal melanoma, the most common primary intra-ocular malignancy in adults. Survival rates for uveal melanoma remain poor. Advances made in the treatment of the primary tumor have not resulted in any improvement in survival rates.1 Up to 50% of patients will develop metastatic disease, even 10–15 years after diagnosis, which invariably leads to death. The median survival of patients with metastasis is less than 6 months. Drugs commonly used to treat cutaneous melanoma, such as dacarbazine, temozolomide, interferon-alfa, and interleukin-2, rarely produce durable responses in patients with uveal melanoma, and to what extent current treatments prolong survival as compared with no treatment at all is not known.2 The resistance of uveal melanoma can be ascribed to its propensity to metastasize to the liver, which is recognized as a particularly refractory site for many cancers, but liver metastases from uveal melanoma may even be less responsive to chemotherapy than liver metastases from cutaneous melanoma.3 Systemic therapy may be more effective in the adjuvant setting treating micrometastatic rather than the macrometastatic disease, where multiple mechanisms of resistance may manifest. Clinical, histologic, and, more recently, cytogenetic factors can be used to identify patients with uveal melanoma harboring micrometastases.4 Administering dacarbazine or interferon-alfa-2b to high-risk patients after primary therapy has not been shown to improve outcome.5, 6
“Targeted therapy” refers to drugs designed to interfere with a specific molecular pathway that is believed to have a critical role in tumor development or progression. The identification of appropriate targets is based on an understanding of the molecular changes underlying the cancer. This approach contrasts with the conventional, more empirical approach used to develop cytotoxic chemotherapeutics and, for the most part, immunotherapeutics. This approach is not new. Hormonal therapies in breast and prostate cancer are examples of targeted therapies. Recent advances in understanding the molecular pathogenesis of cancers, however, have led to a new generation of therapeutic agents. These include drugs that can modify pathways that regulate the cell cycle and whether tumor cells undergo apoptosis or proliferation and drugs that can inhibit molecules involved in invasion and metastasis. These also include drugs that can inhibit tumor angiogenesis, a rate-limiting step in tumor growth and the formation and progression of metastases. Several targeted therapeutics have recently been approved to treat a variety of what had been refractory cancers.
Several targeted therapies are being tested in cutaneous melanoma.7, 8 Whether the drugs under investigation will also be applicable to uveal melanoma is not known. Although there is a common embryologic origin of the melanocytes, there are many differences in clinical and biologic features. Whereas the development of most cutaneous melanoma is strongly linked to exposure to ultraviolet irradiation, the etiology of uveal melanoma remains obscure. The eye lacks lymphatics, and uveal melanoma tends to spread by the hematogenous route, whereas cutaneous melanoma shows a greater predilection for lymphatic metastasis. Furthermore, the molecular pathways altered in development also appear to be quite different (Table 1). A number of molecular changes have been identified in uveal melanoma, and drugs that either directly or indirectly modify these pathways have been developed (Table 2). Clinical trials of some of these are being conducted in patients with uveal melanoma (Table 3). In this review, we have focused on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials.
Section snippets
Molecular pathogenesis
Establishing the molecular pathogenesis of uveal melanoma has been difficult. Uveal melanoma is rarely hereditary, which limits approaches such as linkage analysis to identify susceptibility genes.9 As uveal melanoma is now most often diagnosed clinically and treated with brachytherapy, tissue, particularly from smaller tumors, is not routinely obtained. Thus, it is difficult to develop natural history models for analysis of molecular pathways altered in progression. Furthermore, somatic
Bcl-2
Bcl-2 blocks the mitochondrial release of cytochrome C and prevents the activation of pro-apoptotic caspase proteins. It is influenced by a variety of tumor suppressor pathways, particularly the p53 pathway. Virtually all uveal melanomas have been shown to overexpress Bcl-2. Although tumor Bcl-2 overexpression has been reported to be associated with an unfavorable outcome in cutaneous melanomas,47 tumor Bcl-2 levels have not correlated with other clinical or histologic prognostic parameters or
Adhesion molecules
Cellular adhesion molecules play a central role in metastasis by mediating detachment of cells of the primary tumor and then attachment to components of the extracellular matrix or the vascular endothelium to be invaded. Invasive and noninvasive uveal melanomas have different adhesive properties.96 Uveal melanomas have been characterized by increased expression of a variety of integrins, a family of heterodimeric adhesion molecules that bind ligands by recognizing short amino acid stretches on
FGF-2
Fibroblast growth factors are a family of heparin-binding growth factors that exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including RTK. They also interact with heparan-sulfate proteoglycans and integrins. Uveal melanoma cell lines have been shown to produce FGF-2.46, 110 Immunohistochemistry studies have indicated that FGF-2 is expressed by most uveal melanomas.111 FGF-2 occurs diffusely throughout the tumor and also to be associated with
Summary
Uveal melanoma is a refractory cancer. Systemic treatment options are limited, and at present there are insufficient data to recommend any chemotherapy or immunotherapy program. Targeted therapeutics address molecular abnormalities that are associated with tumor development and progression. This approach has been effectively applied in a broad range of what had been refractory cancers. Although no specific cancer genes have been linked, progress has been made in identifying potential targets
Conflict of interest statement
None of the authors have any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
Acknowledgement
C.E. is the recipient of a Doris Duke Distinguished Clinical Scientist Award.
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