MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells.

The tumor suppressor protein p53 has an important role in cell-fate determination. In cancer cells, the activity of p53 is frequently repressed by high levels of MDMX and/or MDM2. MDM2 is a ubiquitin ligase whose activity results in ubiquitin- and proteasome-dependent p53 degradation, while MDMX inhibits p53-activated transcription by shielding the p53 transactivation domain.

Selective PKCδ Inhibitor B106 Elicits Uveal Melanoma Growth Inhibitory Effects Independent of Activated PKC Isoforms.

In uveal melanoma (UM) cells, the protein kinase C (pathway) is almost generally constitutively activated as a result of an activating mutation in either the GNAQ or the GNA11 G-protein. A pan-PKC inhibitor, sotrastaurin (also named AEB071), is in clinical trials for treatment of UM patients with limited success and eliciting adverse effects. Interestingly, genetic interference with expression of just one PKC isoform, e.

Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target.

Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy.

Targeting MDMX and PKCδ to improve current uveal melanoma therapeutic strategies.

Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients.

Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma.

Very little to no improvement in overall survival has been seen in patients with advanced non-resectable cutaneous melanoma or metastatic uveal melanoma in decades, highlighting the need for novel therapeutic options. In this study we investigated as a potential novel therapeutic intervention for both cutaneous and uveal melanoma patients a combination of the broad spectrum HDAC inhibitor quisinostat and pan-CDK inhibitor flavopiridol. Both drugs are currently in clinical trials reducing time from bench to bedside.