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发病率的持续增加带来了健康和经济挑战。虽然手术对许多患者有效，但需要更有效的非手术治疗选择。通过靶向癌症相关途径开发更好的疗法可能非常有效，如黑色素瘤中的靶向BRAF治疗所示。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，如本申请中所提出的，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INPP 5A基因和蛋白质的损失，在一个显着的 皮肤SCC的比例。我们的初步实验表明，INPP 5A的损失可能是至关重要的SCC生物学和INPP 5A表达的恢复诱导SCC细胞死亡，可能通过调节一个独特的细胞途径，导致肌醇六磷酸（IP 6）的合成。虽然IP 6主要作为谷物中丰富的天然产物进行研究，在几种恶性肿瘤模型中显示出作为潜在抗癌剂的初步功效，但尚未探索内源性细胞INPP 5A途径的改变及其在人类癌症中的作用。因此，探索INPP 5A-IP 6信号通路及其与SCC治疗的相关性是高度创新的。为了解决这些问题，我们将追求以下目标：（1）探索SCC中INPP 5A畸变的总体谱，并将所识别的畸变与临床疾病特征相关联，包括探索INPP 5A在密切相关的头颈部SCC中的更广泛的相关性;（2）评估肌醇途径作为INPP 5A在SCC中作用的主要介质及其对其他细胞途径和过程的影响;以及（3）在动物模型中探索使用其下游产物IP 6来治疗恢复INPP 5A效应。我们希望这些研究能够扩大目前对INPP 5A通路在SCC中所起作用的基本认识，评估该通路作为SCC新治疗方法的调节，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.