Squamous cell carcinoma (SCC) of the skin is one of the most common human malignancies. A continued increase in the incidence of SCC poses both health and financial challenges. Although surgery is effective in many patients, there is a need for more effective non-surgical treatment options. Development of better therapies through targeting of cancer-relevant pathways can be highly effective, as illustrated by targeted BRAF treatment in melanoma. Similarly, we have had a leadership role in development of novel therapeutics for basal cell carcinoma (BCC) based on the understanding of the role of the Hedgehog signaling pathway in BCC. Therefore, characterizing the molecular basis of SCC with a goal of developing novel therapies, as proposed in this application, is of high significance. Thi project will build on our recent work that identified INPP5A gene and protein loss in a significant proportion of cutaneous SCC. Our preliminary experiments indicate that INPP5A loss may be of critical importance for SCC biology and that restoration of INPP5A expression induces death in SCC cells, likely through regulation of a unique cellular pathway leading to synthesis of inositol hexaphosphate (IP6). Although IP6, studied mainly as a natural product abundant in grains, demonstrated preliminary efficacy as a potential anti-cancer agent in several malignancy models, alterations of the endogenous cellular INPP5A pathway and its role in human cancer has not been explored. Thus, exploration of the INPP5A-IP6 signaling pathway and its relevance for treatment of SCC is highly innovative. To address these issues we will pursue the following aims: (1) explore the overall spectrum of INPP5A aberrations in SCC and correlate identified aberrations with the clinical disease characteristics, including exploration of the broader relevance of INPP5A in closely related SCC of head and neck; (2) evaluate the inositol pathway as the principal mediator of INPP5A effects in SCC and its impact on other cellular pathways and processes; and (3) explore therapeutic restoration of INPP5A effects using its downstream product IP6 in animal models. We expect these studies to expand the currently rudimentary knowledge of the role INPP5A pathway plays in SCC, evaluate modulation of this pathway as a novel therapeutic approach in SCC and provide preclinical data necessary to determine feasibility and effectively pursue rationally designed novel treatment approaches for patients with SCC.