Novel Therapeutics Targeting INPP5A Pathway in Squamous Cell Carcinoma

描述(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。鳞状细胞癌发病率的持续增加给健康和财政带来了挑战。虽然手术在许多患者中是有效的，但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是非常有效的，如黑色素瘤的靶向BRAF治疗所表明的那样。同样，基于对Hedgehog信号通路在基底细胞癌中作用的了解，我们在开发新的治疗基底细胞癌(BCC)方面发挥了领导作用。因此，为了开发新的治疗方法，表征鳞状细胞癌的分子基础具有重要的意义。该项目将建立在我们最近的工作的基础上，该工作确定了INPP5A基因和蛋白质在显著 皮肤鳞状细胞癌比例。我们的初步实验表明，INPP5A缺失可能在鳞癌生物学中起关键作用，INPP5A表达的恢复可能通过调节导致六磷酸肌醇(IP6)合成的独特细胞途径而诱导SCC细胞死亡。尽管IP6主要作为一种富含谷物的天然产物在几种恶性肿瘤模型中显示出作为潜在抗癌药物的初步疗效，但内源性细胞INPP5A途径的变化及其在人类癌症中的作用尚未被探索。因此，探索INPP5A-IP6信号通路及其与鳞癌治疗的相关性具有很高的创新性。为了解决这些问题，我们将致力于实现以下目标：(1)探索鳞状细胞癌中INPP5A异常的全部谱系，并将已发现的异常与临床疾病特征相关联，包括探索INPP5A在头颈部密切相关的鳞状细胞癌中的更广泛相关性；(2)评估肌醇途径作为INPP5A在鳞状细胞癌中作用的主要介导者及其对其他细胞途径和过程的影响；以及(3)在动物模型中探索INPP5A作用的治疗恢复。我们期望这些研究将扩大目前对INPP5A通路在鳞癌中所起作用的基本知识，评估该通路作为一种新的治疗方法在SCC中的调节作用，并提供必要的临床前数据，以确定可行性并有效地为SCC患者寻求合理设计的新治疗方法。

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.