Newswise — Researchers have successfully identified two genetic markers for potentially effective treatment of Mesothelioma, an orphan disease most commonly associated with asbestos exposure, and for which few treatments exist. Two recent studies co-authored by researchers from the Sbarro Health Research Organization (SHRO) at Temple University describe the findings of the relationship between p53, BAP1, and Mesothelioma, and the treatment pathways they may reveal.
Published in October, 2018, the paper “p53 Modeling as a Route to Mesothelioma Patients Stratification and Novel Therapeutic Identification,” appeared in the Journal of Translational Medicine, and January, “BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment,” was published in the International Journal of Molecular Sciences.
The studies represent the potential of Personalised Medicine, an innovative approach to clinical medicine meant to customize treatment for an individual patient. In oncology, this most often refers to gene expression-based therapeutic decisions aimed at the identification of “driving genes” responsible for carcinogenesis and tumour progression.
Unfortunately, in the clinical setting, the simple idea of finding one mutated gene causing cancer is rare, and despite some encouraging results, only 4-7% of patients really benefit from treatment based on the tumour genetic profile. Complications such as tumor heterogeneity may determine the poor performance of genetic profiling to reveal effective treatments: different genetic profiles co-exist within the same tumour, epigenetic abnormalities not directly affecting DNA are indirectly responsible for genome expression, and the tumor microenvironment can also exert a pivotal role in gene expression.
In spite of these challenges, researchers have identified ways in which p53, a well-known tumor suppressor gene, may be used to stratify patients for the most favorable treatment protocol. Often referred to as the “guardian of the genome,” p53 functions to limit the proliferation of deformed cells and cells with imperfectly replicated DNA.
The prevalence of p53 inactivation in Mesothelioma prompted researchers to carry out a combined biological and bioinformatic study to explore how data about p53 can be used in translational research. The comparison of model simulations with experimental data resulted in a successful prediction from 52-85%, depending on the drug, algorithm, or sample used for validation.
“This study offers a good approach to test the real impact of genetic studies in precision medicine,” says Luciano Mutti, M.D., Adjunct Professor of Translational Oncology, SHRO, and co-author of the study. “We included in silico and in vitro analysis with cellular validation of the p53 model,” Mutti says, “and we believe it will have a potential for use in Mesothelioma treatment by identifying patient sub-populations that are likely to respond to particular drugs.”
The model may also aid in the identification chemotherapy resistance, the authors conclude, which is common in Mesothelioma.
Mutti collaborated on the study with Marija Krstic-Demonacos, Ph.D., Chair of Molecular Medicine at the University of Salford in Manchester, UK. The authors would like to thank the non-profit association Gruppo Italiano Mesotelioma (GIMe) for their support.
BRCA Associated 1 gene (BAP1) is another tumour suppressor gene recently shown to be inactivated in up to 60% patients with Mesothelioma. Therefore, researchers designed a study to exploit the strictly defined role of BAP1 to repair imperfections in cellular DNA, and tested for indications that BAP1 status could drive chemosensitivity and help identify the right drugs for Mesothelioma treatment. For example, testing the effect of the common Mesothelioma chemotherapy agent, Gemcitibine, on tumor cells with either normal or inactivated BAP1, researchers found that the cells with inactivated BAP1 were resistant to the effects of Gemcitabine, rendering the chemotherapy less effective.
“The results have been unusually clear-cut,” says Antonio Giordano, M.D., Ph.D., Director of SHRO, and co-author of the paper with Mutti, “and further study of BAP1 and p53 can help us identify the best treatment for Mesothelioma in clinical oncology.
“These studies serve as a sign that Personalised Medicine can become an important weapon against Mesothelioma,” Giordano concludes.