P53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1^Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress. Based on publications referenced in PubMed since 2002, here we review the reported effects of these compounds on cancer cells, with a specific focus on their ability of p53 reactivation, an overview of their unexpected anti-cancer effects, and a presentation of the investigated drug combinations.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine involved in the carcinogenesis of many cancer types. Here, we review the published experimental and clinical data for MIF and its involvement in melanoma. All reported data show that MIF is overexpressed in melanoma cells, especially in case of metastatic disease. Clinical studies also indicate that high MIF expression is positively associated with aggressiveness of the disease. Some data also highlight the implication of MIF in angiogenesis, immunity and metastasis in melanoma cell lines, as well as the availability of different therapeutic options targeting MIF for the treatment of metastatic melanoma. Indeed, the main problem in metastatic melanoma is the lack of long-term effective treatment. This is linked to the capacity of melanoma cells to mutate very quickly and/or activate alternative signaling pathways. Thus, MIF targeting therapies could provide a new effective way of treating melanoma. Moreover, cell sensitivity to MIF depletion does not correlate with the BRAF mutational status. Regarding the fact that many melanoma patients carry a BRAF mutation, and that they develop resistance to BRAF inhibitors, this observation is very interesting as MIF inhibitors could be used to treat many patients in relapse after treatment with an inhibitor of the mutant BRAF protein.

Clinical outcome of patients with high-risk melanoma cannot be reliably predicted on the basis of classical histopathological examination. Our study aimed to determine in melanoma metastases a gene expression profile associated with patient survival, and to identify and validate marker(s) of poor clinical outcome. Skin and lymph node metastases from melanoma patients (training population) were used to identify candidate prognostic marker(s) based on DNA microarray analysis. Additional skin metastases (validation population) were used to assess the prognostic value of the first ranked gene by real-time PCR. We performed microarray analysis in the training population and generated a list of 278 probe sets associated with a shorter survival. We used the first ranked gene, tyrosinase-related protein 1 (TYRP1), further measured its expression in the validation population by real-time PCR and found it to be significantly correlated with distant metastasis-free survival (DMFS), overall survival (OS) and Breslow thickness. We also found that it was fairly well conserved in the course of the disease regardless of the delay to metastasis occurrence. Finally, although Tyrp1 protein (immunohistochemistry (IHC)) was only detected in about half of the samples, we showed that its expression also correlated with Breslow thickness. Our data indicate that TYRP1 mRNA expression level, at least in skin metastases, is a prognostic marker for melanoma, and is particularly useful when prognostic pathology parameters at the primary lesion are lacking. Its conserved expression further supports its use as a target for therapy.