p53 modeling as a route to mesothelioma patients stratification and novel therapeutic identification.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types of cancer. Most chemotherapeutics cause DNA damage leading to cell death. Recent discoveries have highlighted a potential role for the p53 tumor suppressor in this disease. Given the pivotal role of p53 in the DNA damage response, here we investigated the predictive power of the p53 interactome model for MPM patients' stratification. METHODS: We used bioinformatics approaches including omics type analysis of data from MPM cells and from MPM patients in order to predict which pathways are crucial for patients' survival. Analysis of the PKT206 model of the p53 network was validated by microarrays from the Mero-14 MPM cell line and RNA-seq data from 71 MPM patients, whilst statistical analysis was used to identify the deregulated pathways and predict therapeutic schemes by linking the affected pathway with the patients' clinical state. RESULTS: In silico simulations demonstrated successful predictions ranging from 52 to 85% depending on the drug, algorithm or sample used for validation. Clinical outcomes of individual patients stratified in three groups and simulation comparisons identified 30 genes that correlated with survival. In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival. Numerous repositioned and experimental drugs targeting FEN1 and MMP2 were identified and selected drugs tested. Epinephrine and myricetin, which target FEN1, have shown cytotoxic effect on Mero-14 cells whereas marimastat and batimastat, which target MMP2 demonstrated a modest but significant inhibitory effect on MPM cell migration. Finally, 8 genes displayed correlation with disease stage, which may have diagnostic implications. CONCLUSIONS: Clinical decisions related to MPM personalized therapy based on individual patients' genetic profile and previous chemotherapeutic treatment could be reached using computational tools and the predictions reported in this study upon further testing in animal models.

The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.

The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data. The public version of HGMD ( http://www.hgmd.org ) is freely available to registered users from academic institutions and non-profit organisations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via QIAGEN Inc.

Tremelimumab for the treatment of malignant mesothelioma.

INTRODUCTION: Tremelimumab demonstrated therapeutic activity in different malignancies, including malignant pleural mesothelioma (MPM); however, continued research could improve the therapeutic index of this agent. AREAS COVERED: This review describes tremelimumab's clinical efficacy, administration and safety in patients affected with MPM and reports the state of the art clinical trials of tremelimumab. A literature search using the PubMed database was conducted using the search terms tremelimumab, MPM, current therapy, immune checkpoint blockage and cytotoxic T lymphocyte-associated antigen-4. Data was also obtained from meeting abstracts and clinical trial registries. EXPERT OPINION: The use of immunotherapy has been extended from melanoma to thoracic malignancies or lung cancer and MPM. The first clinical trials for MPM with drugs modulating immune checkpoints have been tested or are currently being tested with the first results now under critical consideration. Among these drugs, tremelimumab has been attracting attention as a potential new treatment for MPM. Nevertheless, even though clinical efficacy has been preliminarily demonstrated, the cost/benefit ratio of this drug for this neoplasm is yet to be ascertained.