Reversion of anti-viral status in human tumors

Oncolytic viral therapy is becoming an interesting alternative to standard therapies for incurable diseases. Our group has demonstrated the existence of two distinguishable phenotypes based on the expression of interferon-stimulated genes (ISGs) and Virus Stress Induced Genes (VSIG) with Myxovirus-resistance-A (MxA) protein as a marker. The existence of this ISGs phenotype has been proved to block viral oncolysis and viral mediated gene expression in cancer cells. We demonstrated that this caused in vivo an acquisition of a viral resistant phenotype in recurrent tumors cured in the first place with adeno-mediated oncolytic therapies. This is a phenomenon shared in both, solid and hematological tumors as well. The understanding of the mechanism that induces the expression of this interferon-related signature became of a key importance in optimizing oncolytic and gene therapies. In order to discover the pathways involved in the tumor-acquired ISGs phenotype, we focused our attention on tumor cell lines, and in particular pancreatic cancer and multiple myeloma cancer cell lines in vitro. Pancreatic ductal adenocarcinoma represents one of the most vicious cancers, for which no effective cure is optimised. On the other hand, multiple myeloma is the most frequent hematological tumor in humans and was often used as a possible target tumor for virus based therapies. The main aim of the present work was to confirm the existence of the dualism of ISGs phenotype in different cancer models and dissect the most important interferon pathways by specifically silencing different steps that could be responsible for the downstream ISGs up-regulation. We focused our attention to NFkB pathway in PDAC cancer cells and STAT3 pathway in multiple myeloma. We conclude that ASA and curcumin treatement can effectively revert the resistance in PDAC cell lines, while only resveratrol treatment can affect the infectivity of multiple myeloma cell lines to adenoviral vectors. Those findings can be considered the rational for a combinatory therapy with the aim of increasing the efficacy of oncolytic or gene therapy adeno-based approaches that might constitute the future for curing incurable cancers as pancreatic ductal adenocarcinoma.