Abstract 3747: Oncolytic viruses as a possible therapeutic strategy against malignant mesothelioma
Authors: Iannuzzi Carmelina Antonella , Passaro Carmela , Boffo Silvia , Forte Iris Maria , Indovina Paola , Macaluso Marcella , Portella Giuseppe , Giordano Antonio , Pentimalli Francesca 
Published: July 2016

Abstract
Malignant mesothelioma (MM) is a very aggressive tumor associated to asbestos exposure, which is poorly responsive to the current therapeutic strategies, resulting in a dismal prognosis. So, considering also that various studies predict an increase in incidence, new effective therapeutic approaches are urgently needed. Here we investigated at the preclinical level a new possible therapeutic strategy for MM based on the use of oncolytic viruses. Oncolytic viruses show various benefits as anticancer agents: they can replicate selectively in tumor cells reaching 10,000-fold amplification of the input dose; they stimulate the antitumoral immune response; they can be used in combination with other cytotoxic agents; the pleural cavity in which pleural MM arises is easily accessible for such therapeutic approach. In particular, we focused on adenoviruses with a 24 bp deletion in the E1A-conserved region 2, which binds and inactivates the retinoblastoma protein, resulting in a virus (dl 922-947) 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 epithelioid NCI-H28 and NCI-H2452, the biphasic MSTO-211H, the sarcomathoid NCI-H2052 — the effects of dl 922-947 treatment used both as a single agent or in combination with other strategies. At first, dl 922-947 cytotoxicity was evaluated through the sulforhodamine B (SRB) assay, which showed that all MM cell lines were susceptible to viral treatment, except NCI-H2052 cells, in which viral entry was not efficient, as shown through infection with a reporter adenovirus transducing GFP. 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 by SRB the possible cytotoxic effects of dl922-947 in combination with other therapeutic strategies. In particular, we analyzed the effect of dl922-947 in combination with cisplatin, which is the first-line treatment against MM, and found that, by comparing different schedules of treatment, cisplatin increased the cytotoxic effect of the oncolytic virus. We also tested dl922-947 efficacy in combination with MK-1775, an efficient inhibitor of the WEE1 kinase, which is currently being tested in clinical trials. We found that MK-1775, at doses equal to or above its IC50value, is able to increase the cytotoxic effect of the oncolytic virus 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.
Citation Format: Carmelina Antonella Iannuzzi, Carmela Passaro, Silvia Boffo, Iris Maria Forte, Paola Indovina, Marcella Macaluso, Giuseppe Portella, Antonio Giordano, Francesca Pentimalli. Oncolytic viruses as a possible therapeutic strategy against malignant mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3747.