Novel therapeutic strategies and targets in advanced uveal melanoma

Purpose of review Currently, there are no U.S. Food and Drug Administration-approved or effective treatment options for advanced-stage uveal melanoma. In this article, we focus on therapeutic targets in pathways/mechanisms associated with common mutations in uveal melanoma. We review the challenges associated with targeting of these pathways and novel treatment strategies. Recent findings Common mutations that promote uveal melanoma initiation and progression include alterations in G protein subunit alpha q/11 (GNAQ/GNA11) and breast cancer gene 1-associated protein 1 (BAP1). Mutant GNAQ/GNA11 induces constitutive activation of tumorigenic pathways such as extracellular signal-regulated kinase (ERK)1/2 and yes-associated protein. Inhibition of mitogen-activated protein kinase kinase (MEK) downstream of ERK1/2, however, was shown in trials to have limited clinical benefit. Recent reports suggested that combination therapies of MEK inhibition and modulators of mechanisms of drug resistance may improve tumor responses to MEK inhibitors. BAP1 has been shown to be involved in modulating chromatin dynamics and deubiquitination of proteins. Hence, epigenetic inhibitors are being investigated in BAP1 mutant uveal melanoma. However, other functions of BAP1, such as in DNA damage repair and cell cycle regulation, indicate additional targets for treatment of BAP1 mutant uveal melanoma. In addition, the frequent delayed development of uveal melanoma macrometastases is likely due to ...
Source: Current Opinion in Oncology - Category: Cancer & Oncology Tags: MELANOMA AND OTHER SKIN NEOPLASMS: Edited by Reinhard Dummer Source Type: research