Mesothelioma is a very aggressive cancer associated with asbestos exposure, which is usually diagnosed in an advanced stage. So far no therapeutic strategy has proven effective against this deadly cancer and the prognosis remains very poor with only few exceptions.
In December, the research team of Antonio Giordano, a pathologist, Director and Founder of the Sbarro Health Research Organization in Philadelphia, PA, and Professor of Pathology and Oncology at the University of Siena, Italy, published two separate studies aiming to address the urgent need to identify possible new methods for mesothelioma treatment.
In the first study, published in the scientific journal Cell Cycle, Giordano's researchers tested on mesothelioma cells the effect of two drugs designed to reactivate the p53 protein, one of the most important 'tumor suppressors', which is turned off in most human cancers. "In mesothelioma, although p53 is rarely mutated, it is inactivated by alterations in its pathway," says Francesca Pentimalli of the National Cancer Institute of Naples, Italy, lead author of the study. Both of the drugs used in the study target p53, but with different mechanisms of action. One in particular, called RITA, proved to be very toxic. Specifically, RITA caused mesothelioma cells, and not 'healthy' cells, to undergo apoptosis -- a type of programmed cell death that occurs through the activation of a specific 'cascade' of events.
"The ability of RITA to induce apoptosis is remarkable considering that mesothelioma is very refractory to this process. In fact the most aggressive and rare variant, sarcomatoid mesothelioma, did not respond to the treatment probably because of its intrinsically high levels of molecules acting as inhibitors of this process" says Alfredo Budillon, Head of the Experimental Pharmacology Unit of the National Cancer Institute of Naples and coauthor of the study. "It remains to be seen whether the combination of RITA with other activators of apoptosis can achieve efficacy also against the more aggressive cases."
Furthermore, challenging mesothelioma cells with RITA worked in synergy with the chemotherapy drug cisplatin, which is the mainstay of treatment for this disease, suggesting that its use in a clinical setting could possibly help to reduce the required doses and the side effects of chemotherapy, thereby improving patients' quality of life.
The second study, published online in Cancer Biology and Therapy and led by Paola Indovina of the University of Siena and the Sbarro Institute for Cancer Research and Molecular Medicine, Temple University in Philadelphia, was designed along the same lines as the first study. In the second study, the authors tested, for the first time in mesothelioma, a new drug called MK-1775 in combination with cisplatin. MK-1775 is a selective inhibitor of WEE1, a protein that is crucial in activating a 'checkpoint' for the repair of damaged DNA before the cell starts its division process. The rationale for this strategy is based on the fact that many cancer cells, especially those with non-functional p53, rely on WEE1 to stall cell division and allow cells to repair the damage induced by genotoxic agents, such as many chemotherapeutic drugs, including cisplatin. WEE1 inhibition limits the time available for repair and, therefore, sensitizes cancer cells to DNA-damaging agents. Indeed, inhibiting WEE1 with MK-1775 selectively sensitized mesothelioma cells to the genotoxic action of cisplatin by preventing checkpoint activation and forcing the cells to divide despite the damage, thus triggering apoptosis.
"Overall our studies are aimed at identifying promising new molecular therapies against mesothelioma that hold the potential for clinical use in the near future. MK-1775, for example, is already being utilized in clinical trials for other types of tumors in the United States," Giordano concludes.
- Paola Indovina, Eleonora Marcelli, Domenico Di Marzo, Nadia Casini, Iris Maria Forte, Francesca Giorgi, Luigi Alfano, Francesca Pentimalli, Antonio Giordano. Abrogating G2/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma. Cancer Biology & Therapy, 2014; 15 (4) DOI: 10.4161/cbt.27623
- Domenico Di Marzo, Iris Maria Forte, Paola Indovina, Elena Di Gennaro, Valeria Rizzo, Francesca Giorgi, Eliseo Mattioli, Carmelina Antonella Iannuzzi, Alfredo Budillon, Antonio Giordano, Francesca Pentimalli. Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma. Cell Cycle, December 2013
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