Oncolytic viruses as a possible therapeutic strategy against malignant mesothelioma

Malignant mesothelioma (MM) is a highly aggressive cancer for which, at present, no curative modalities exist. MM in fact is poorly responsive to the current therapeutic strategies, resulting in a dismal prognosis. New alternative therapeutic approaches are therefore urgently needed. Here we aimed at investigating at the preclinical level whether oncolytic viruses could represent a feasible strategy. We focused on the dl 922-947 adenovirus having a 24 bp deletion in the E1A-conserved region 2, which binds and inactivates the retinoblastoma protein, resulting in a virus that cannot trigger S phase entry in normal cells, but can still replicate in cells with an aberrant G1-S checkpoint, a defect observed in over 90% human cancers, including MM. We studied on a panel of mesothelioma cell lines representative of the main different histotypes, the effects of dl 922-947 treatment used both as a single agent or in combination with other strategies (cisplatin and MK-1775). Interestingly and consistently with the cytotoxic effect observed, FACS analysis showed that dl 922-947 treatment induced an increase of the subG1 cell fraction (suggestive of apoptosis induction) and of the hyperdiploid (4N) population (suggestive of mitotic defects). We also investigated the possible cytotoxic effects of dl922-947 in combination with cisplatin, which is the first-line treatment against MM, and MK1775, which, by forcing cells into mitosis, might increase cell death of infected cells. Preliminary results show that both combinations increase the cytotoxic effect of the OV treatment. In conclusion our data indicate that treatment with the dl922-947 oncolytic virus might be a promising new approach against mesothelioma and warrants further investigation both as single agent and in combination strategies.