ABSTRACT
Most uveal melanomas harbor mutations in Gαq and show constitutive MAPK activation. Although MEK inhibition has some efficacy against uveal melanoma, clinical responses are typically poor. The Gαq inhibitor-MEK inhibitor combination showed prolonged suppression of MAPK signaling in preclinical uveal melanoma models and led to improved therapeutic responses.See related article by Hitchman et al., p. 1476.
Subject(s)
Melanoma , Uveal Neoplasms , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Humans , Melanoma/drug therapy , Melanoma/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Uveal Neoplasms/drug therapy , Uveal Neoplasms/geneticsABSTRACT
Different animal models have been proposed to investigate the mechanisms of Human T-lymphotropic Virus (HTLV)-induced pathogenesis: rats, transgenic and NOD-SCID/γcnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques. These systems indeed provide useful information but have intrinsic limitations such as lack of disease relevance, species specificity or inadequate immune response. Another strategy based on a comparative virology approach is to characterize a related pathogen and to speculate on possible shared mechanisms. In this perspective, bovine leukemia virus (BLV), another member of the deltaretrovirus genus, is evolutionary related to HTLV-1. BLV induces lymphoproliferative disorders in ruminants providing useful information on the mechanisms of viral persistence, genetic determinants of pathogenesis and potential novel therapies.
Subject(s)
Host-Pathogen Interactions , Human T-lymphotropic virus 1/physiology , Leukemia Virus, Bovine/physiology , Animals , Biomedical Research/trends , Disease Models, Animal , Human T-lymphotropic virus 1/pathogenicity , Humans , Leukemia Virus, Bovine/pathogenicity , Virology/trendsABSTRACT
Malignant pleural mesothelioma (MPM) is an almost invariably fatal cancer of the pleura due to asbestos exposure. Increasing evidence indicates that unresponsiveness to chemotherapy is due to epigenetic errors leading to inadequate gene expression in tumor cells. The availability of compounds that modulate epigenetic modifications, such as histone acetylation or DNA methylation, offers new prospects for treatment of MPM. Here, we review latest findings on epigenetics in mesothelioma and present novel strategies for promising epigenetic therapies.