This application is based on ADT Pharmaceuticals' discoveries that: 1) the cGMP degrading phosphodiesterase isozyme, phosphodiesterase 10A (PDE10), is overexpressed during early stages of tumorigenesis; 2) genetic knockdown of PDE10 results in selective apoptosis of tumor cells by activating cGMP/PKG signaling; and 3) small-molecule inhibitors of PDE10 induce apoptosis by PKG phosphorylation of oncogenic ?-catenin, thereby suppressing Tcf-mediated transcription of genes that encode for proteins, such as survivin, essential for tumor cell survival. From a completed Phase I SBIR project involving a medicinal chemistry and screening campaign with follow-up chemical optimization, ADT Pharmaceuticals developed a novel PDE10 inhibitor, ADT-030, which concentrates in lungs following oral administration. ADT-030 showed strong antitumor activity without discernable toxicity in multiple highly aggressive mouse models of lung cancer, including a chemical-induced mouse model of cancer chemoprevention. Here we propose studies to evaluate a clinically amenable oral formulation of ADT-030 that we hypothesize will be ideal for lung cancer chemoprevention in humans. We expect ADT-030 will be safe and efficacious for lung cancer chemoprevention by achieving high local concentrations in lungs with low systemic levels.
