Malignant pleural mesothelioma (MPM) is a very aggressive cancer mainly caused by exposure to asbestos, against which no curative modalities exist, although many different strategies have been attempted so far.
A study exploring a new combination of therapeutic agents, dl922-947, an oncolytic adenovirus, and AZD1775, an inhibitor of the DNA damage checkpoint kinase WEE1, has been published in the International Journal of Molecular Sciences. The authors include a team of researchers coordinated by Antonio Giordano, Director and Founder of the Sbarro Health Research Organization (SHRO) in Philadelphia, and Professor of Pathological Anatomy at the University of Siena, Italy, working in collaboration with the team of Professor Giuseppe Portella of the University of Naples Federico II. Both these agents showed to be promising for MPM treatment in previous preclinical studies by the same group of researchers, in particular when combined with cisplatin, the drug currently used in MPM chemotherapy. The rationale behind this new dl922-947-AZD1775 combination strategy is that, among the mechanisms of dl922-947 action, this virus induces DNA lesions in the host cells; these lesions in turn activate the host DNA damage repair pathways, which can counteract viral action. Thus, the inhibition of this cell response can enhance the effects of dl922-947. Indeed, the authors found that AZD1775, by inhibiting the WEE1-mediated DNA damage checkpoint, sensitized MPM cells to dl922-947.
“We found that AZD1775 synergized with dl922-947 in MPM cell lines, without affecting normal mesothelial cells, and increased dl922-947-induced MPM cell death, which showed hallmarks of apoptosis,” says Carmelina Antonella Iannuzzi of the National Cancer Institute of Naples, Pascale Foundation, first author of the study. “This is remarkable since MPM cells are very refractory to this cell death process.”
“Both dl922-947 and AZD1775 were conceived to selectively affect cancer cells in which crucial tumor suppressor pathways are inactive, while sparing normal cells in which these pathways are functional,” adds Paola Indovina of the Sbarro Health Research Organization, co-first author of the study. “Thus, the combination of these agents could be an optimal approach against a tumor, such as MPM, that mainly develops through the loss of tumor suppressor functions.”
“Although the efficacy of dl922-947-AZD1775 combination has yet to be assessed in animal models, this strategy holds the potential for clinical translation; indeed MPM is a good candidate for virotherapy because the pleural location provides direct access for the intra-tumoral injection of the virus and both AZD1775 and virotherapy-based approaches are already in clinical trials for other tumor types,” concludes Francesca Pentimalli of the National Cancer Institute of Naples, Pascale Foundation, corresponding author of the study.
About the Sbarro Health Research Organization
The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org