Novel Therapeutics Targeting INPP5A Pathway in Squamous Cell Carcinoma

描述（由申请人提供）：皮肤鳞状细胞癌（SCC）是最常见的人类恶性肿瘤之一。SCC发病率的持续增加给健康和财政带来了挑战。虽然手术对许多患者有效，但仍需要更有效的非手术治疗方案。通过靶向癌症相关途径开发更好的治疗方法可能非常有效，如靶向BRAF治疗黑色素瘤。同样，基于对Hedgehog信号通路在基底细胞癌（BCC）中的作用的理解，我们在开发基底细胞癌（BCC）的新疗法方面发挥了领导作用。因此，以开发新疗法为目标来表征SCC的分子基础具有重要意义。该项目将建立在我们最近的工作，确定了INPP5A基因和蛋白质的显著损失

DESCRIPTION (provided by applicant): 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.