Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives

Abstract

Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas BRAFV600E-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, BAP1 loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy.

The Role of Immune Checkpoint Blockade in Uveal Melanoma

“…However, the median OS was not different between both groups (13 months with sorafenib vs. 12.2 months with placebo) [74]. Other targeted treatment approaches have also shown no promising results, as recently reviewed in [75,76].…”

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

“…Surgical resection is the main therapeutic approach for patients with early melanoma. Given the high malignancy degree of patients with melanoma in advanced stages, the effect of standardized treatment is poor, and the accompanying diagnosis and individualized targeted therapy have become important strategies [1][2][3][4][5][6][7][8]. Several kinase inhibitors, including BRAF inhibitor vemurafenib and dabrafenib, MEK1/2 inhibitor trametinib, c-kit inhibitor imatinib and nilotinib, and other inhibitors targeted to the PI3K/Akt/mTOR signaling pathways, have been approved for the treatment of metastatic melanoma [9][10][11][12][13].…”

Uveal Melanoma

“…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, namely G protein subunit alpha Q (GNAQ) and G protein subunit alpha 11 (GNA11) [2,3], 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 [4]. More recently, the HIPPO-independent activation of the YAP/TAZ signaling pathway by mutated GNAQ and GNA11 has been described [5,6] but, at present, no specific inhibitors have been tested in the clinics.…”

“…In the present thematic issue, the authors of 44 articles (31 original research articles [10,13,, 11 reviews [4,11,12,14,[47][48][49][50][51][52][53], one position paper [54], and one network report [55]) give insight into the current state of our understanding of uveal melanoma biology and clinics. They also discuss opportunities for the development of new therapeutics that will hopefully soon improve the survival rates of metastatic uveal melanoma patients.…”

“…Violanti et al offer a different perspective on the molecular oncogenesis of uveal melanoma and the implications for therapy [53]. Croce et al focus their review on targeted therapies that have not met with success in the clinics and try to give a perspective for future approaches to targeted therapy [4].…”