Special Issue "Uveal Melanoma"
A special issue of Cancers (ISSN 2072-6694).
Deadline for manuscript submissions: closed (30 June 2019).
Uveal melanoma is among the best characterized solid tumors. It has become clear that there are mainly two subtypes that can eventually be subdivided into three or four, which are clearly distinct by their histopathological, cytogenetic, and molecular characteristics. The analysis of the subtypes allows to prognosticate the metastatic risk of each patient with an unmatched accuracy. While we essentially understand the molecular steps in uveal melanoma carcinogenesis, the mechanisms of metastasization and pronounced liver tropism are still poorly understood.
Unfortunately, the diagnostic and prognostic power is not matched by efficacy of therapy. The primary tumor is controlled by radiological and surgical interventions and local relapses are extremely rare. Nevertheless, approximately half of the patients develop metastases that rapidly progress to the fatal stage. Despite research, survival of patients with metastatic uveal melanoma has not changed over decades. The identification of the most frequent putative driver mutations, which occur in a mutually exclusive manner in two genes encoding alpha-subunits of G-proteins GNAQ and GNA11, has indicated G-protein signaling and the activation of MAP-kinases as potential targets, but MEK-inhibitors have failed to show major effects in clinical trials. More recently, the HIPPO independent activation of the YAP/TAZ signaling pathway by mutated GNAQ and GNA11 has been described, but, at present, no specific inhibitors have been tested in clinics. Recent reports on a specific inhibitor of the mutated form of GNAQ must be confirmed and translated into clinical applications. Immune checkpoint blockers that have met considerable success in the treatment of several cancers, including cutaneous melanoma, show very low response rates in uveal melanoma, likely due to the low number of neo-antigens, a consequence of a very low mutational burden.
Just like for other cancers, the identification of its Achilles’ heel will rely on a deep understanding of the molecular and cellular features of the cancer cell in its permissive microenvironment. This will likely be possible by the thorough molecular characterization of ever more tumors, the development of better cellular and animal models, such as three dimensional cultures, organoids, and patient derived xenografts, and the testing of new drugs, whether targeted at the molecular lesions typical of metastatic uveal melanoma or at the immune system.
In the present thematic issue, we try to summarize the current state of our understanding of uveal melanoma biology and recent advancements in uveal melanoma therapy and we discuss opportunities for therapeutic interventions that will hopefully soon improve the survival rates of metastatic uveal melanoma patients.
Dr. Ulrich Pfeffer
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