Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Uveal Melanoma Metastasis

Version 1 : Received: 28 September 2021 / Approved: 1 October 2021 / Online: 1 October 2021 (11:54:23 CEST)

How to cite: Rossi, E.; Croce, M.; Reggiani, F.; Schinzari, G.; Ambrosio, M.; Gangemi, R.; Tortora, G.; Pfeffer, U.; Amaro, A. Uveal Melanoma Metastasis. Preprints 2021, 2021100013 (doi: 10.20944/preprints202110.0013.v1). Rossi, E.; Croce, M.; Reggiani, F.; Schinzari, G.; Ambrosio, M.; Gangemi, R.; Tortora, G.; Pfeffer, U.; Amaro, A. Uveal Melanoma Metastasis. Preprints 2021, 2021100013 (doi: 10.20944/preprints202110.0013.v1).

Abstract

Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovate therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of MEK-inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM) show only marginal effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers and YAP/TAZ specific drugs give new hope to repeat the success of innovative therapy obtained for CM.

Keywords

uveal melanoma; tumorigenesis; molecular classification; targeted therapy; immune checkpoint; tumor heterogeneity

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