Enhanced CRAd for Pancreatic Cancer

Pancreatic cancer is one of the most aggressive malignancies with a devastating prognosis. Conditionally replicative adenovirus (CRAd) is a promising therapeutic modality for pancreatic cancer. CRAd clinical trials to date have established the safety of these agents and identified their current limitations. To address these limitations, we have developed a series of infectivity-enhanced, promoter-controlled CRAds resulting in one candidate (RGDCOXCRAdF) which is currently in preclinical toxicological studies for clinical trial. Recent advancement in pancreatic cancer molecular biology has identified several target worthy molecular features: k-RAS activating mutation, human telomerase (TERT) upregulation, mesothelin overexpression, and Cox-2 induction. In addition to target specificity, CRAd therapeutic effect could be further augmented by outfitting them with anti-tumor effectors for pancreatic cancer (e.g., interferon-[unreadable]nd soluble-transforming growth factor (TGF)-feceptor). We propose a new generation pancreatic cancer CRAd design with disease selectivity and therapeutic potency by exploiting the specific molecular features of this disease. In addition to vector design, the models with close relevance to the clinical settings of this disease will be employed for vector evaluation. In the context of murine models, we will employ an orthotopic pancreatic cancer xenograft model as well as a conventional subcutaneous xenograft model. As another model, a hamster syngeneic pancreatic cancer model will provide deeper insight about the biology of CRAd because this system allows various assessments in immunocompetent animals supporting human adenoviral replication. Furthermore, optical monitoring capability will be incorporated into the vector design to allow non-invasive detection of viral replication and therefore CRAd biology. Lastly, our recent establishment of CRAd function analysis based on tissue slice technology would allow us to evaluate our CRAds in patient materials with maintained tissue integrity. The validation of our methods would establish the foundation for rapid clinical translation of a novel and effective CRAd-based strategy for the treatment of pancreatic cancer.