Two new drugs act on the treatment of mesothelioma

Two new drugs act on the treatment of mesothelioma

Malignant mesothelioma is an aggressive cancer disease. This tumor is usually diagnosed at an advanced stage and affects the pleural and peritoneal cavity. Early diagnosis is difficult because more than 50 systemic or pulmonary illnesses are clinically illuminated. So far, no therapeutic strategy has proven its effectiveness against lethal cancer and the prognosis remains very poor with some minor exceptions.

In December, the research team of Antonio Jordano, a pathologist, director and founder of the Health Research organization in Philadelphia, and a professor of pathology and cancer at the University of Siena, Italy, published two separate studies. They are aimed at resolving urgent issues related to possible new methods for treating mesothelioma.


In the first study published in the journal Cell Cycle , researcher Antonio Jordano made a clinical study on mesothelioma cells. The effect of two drugs designed to reactivate the p53 protein is monitored. This protein is one of the most important "tumor suppressors." It is inactive in most cancers in humans.

In mesothelioma, although p53 rarely mutates, it is inactivated by various changes. Francesca Pentimali of the National Cancer Institute of Naples, Italy, lead author of the study, believes that both drugs used in the p53 study are working but with different mechanisms of action. One drug, called RITA, has been shown to be very toxic. In particular, RITA causes mesothelioma cells, not healthy cells, to apoptosis - a type of programmed cell death that is manifested by the activation of a specific "cascade" of events.


Another scientist, Alfredo Budillon, head of the department of pharmacology at the National Cancer Institute in Naples and co-author of the study, believes RITA's ability to trigger apoptosis is remarkable. This is because mesothelioma is refractory to programmed cell death, that is, insensitive. In fact, the most severe and rare type of mesothelioma, the sarcomatoid, does not respond to treatment, probably because of its inherently high levels of molecules that act as inhibitors of this process.

It remains to be investigated whether a combination of RITA and other apoptosis activators can be effective against more aggressive cases.
In addition, mesothelioma cells treated with RITA work in conjunction with chemotherapy . It uses cisplatin, which is the basis for the treatment of this disease, suggesting that its use in clinical conditions could help reduce the required doses and side effects of chemotherapy. This will improve the quality of life of patients.

The second study, published online in Cancer Biology and Therapy, led by Paula Indovina of the University of Siena and the Institute for the Study of Cancer (Italy), was designed in the same way as the first study. In the second study, a new drug called MK-1775 in combination with cisplatin in mesothelioma was first tested .


MK-1775 is a selective inhibitor of WEE1. A WEE1 is a protein that is critical in activating a "site" for repairing damaged DNAs before the cell starts its division process.

The main reason for this strategy is based on the fact that many cancer cells, especially those with non-functional p53, rely on WEE1 to delay cell division and allow cells to repair damage. These lesions are induced, i.e. induced by genotoxic agents, such as many chemotherapeutic drugs, including cisplatin. WEE1 inhibition limits the time required for repair, and therefore affects the cancer cells of DNA-damaging agents. In fact, inhibition of WEE1 with MK-1775 forces the cells to divide despite the damage to them, thus causing apoptosis.


The team's research is aimed at identifying new molecular therapies against mesothelioma that have the potential for clinical use in the near future. MK-1775, for example, is already being used in clinical trials for other types of tumors in the United States.

Bibliography


1. 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 & amp; Therapy, 2014; 15


2. 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