TOPIC 386: NOVEL ORALLY BIOAVAILABLE PDE -CATENIN INHIBITOR CONCENTRATES IN LUNG FOR CANCER CHEMOPREVENTION

This application is based on ADT Pharmaceuticalsdiscoveries thatthe cGMP degrading phosphodiesterase isozymephosphodiesteraseAPDEis overexpressed during early stages of tumorigenesisgenetic knockdown of PDEresults in selective apoptosis of tumor cells by activating cGMP PKG signalingandsmall molecule inhibitors of PDEinduce apoptosis by PKG phosphorylation of oncogeniccateninthereby suppressing Tcf mediated transcription of genes that encode for proteinssuch as survivinessential for tumor cell survivalFrom a completed Phase I SBIR project involving a medicinal chemistry and screening campaign with follow up chemical optimizationADT Pharmaceuticals developed a novel PDEinhibitorADTwhich concentrates in lungs following oral administrationADTshowed strong antitumor activity without discernable toxicity in multiple highly aggressive mouse models of lung cancerincluding a chemical induced mouse model of cancer chemopreventionHere we propose studies to evaluate a clinically amenable oral formulation of ADTthat we hypothesize will be ideal for lung cancer chemoprevention in humansWe expect ADTwill be safe and efficacious for lung cancer chemoprevention by achieving high local concentrations in lungs with low systemic levels