Targeting Fibroblast Growth Factor Receptor-2b in prevention and treatment of cutaneous Squamous cell carcinoma.

皮肤鳞状细胞癌(CSCC)是美国发病率增长最快的癌症之一。 每年20万美国人。暴露于太阳UVB(紫外线B)辐射是导致 皮肤癌。在器官移植患者中，CSCC的发生率比 普通人口。在其他常见的皮肤癌中也发现了靶向药物，如基底细胞癌 癌和黑色素瘤，但不是CSCC。因此，需要新的基于机制的有针对性的方法 用于预防和治疗侵袭性CSCC。此外，切除头颈部的颈鳞状细胞癌会导致 严重的面部毁容，从而对死皮患者进行化学预防是至关重要的。在我们的 成纤维细胞生长因子受体(FGFR)的初步研究、全身应用和局部应用 拮抗剂AZD4547可显著抑制UVB诱导的SKH-2大鼠表皮增生和过度增殖。 1只小鼠。此外，抑制FGFR与下调mTOR和AKT信号有关 路径。AZD4547还抑制CSCC细胞的存活、迁移和运动，从而导致肿瘤减少 体内异种移植模型中的生长。有趣的是，FGFR受体亚型FGFR2的缺失显著 CSCC细胞中mTOR和AKT信号的降低提示FGFR2在 AZD4547介导的效应。先前发表的研究表明，FGFR2b在皮肤中具有保护作用。 然而，重要的是要了解FGFR2b在皮肤中的作用是高度依赖于上下文的 需要关键的实验来清楚地确定它在UVB诱导的皮肤癌发病机制中的作用。 根据我们的初步数据，我们的中心假设是针对FGFR，并选择性地针对FGFR2 对预防CSCC至关重要。因此，在Aim1中，我们将确定AZD4547对 UVB诱导的急性表皮增生和过度增殖。此外，我们还将评估影响 AZD4547对UVB诱导的肿瘤促进和进展的影响。AIM2将确定以下时间进程 UVB诱导FGFR激活，并评估抑制FGFR对下游FGFR信号的影响。 使用K14.CreerT2 x FGFR2bFLOX/FLOX小鼠，FGFR2b在调节UVB诱导的mTORC1和 还将评估AKT的激活情况。此外，UVB诱导的FGFR2配体的来源和类型 皮肤也将被研究。AIM3将主要致力于确定FGFR2在UVB诱导的 表皮增生、细胞凋亡与皮肤癌的发生。此外，FGFR2在抑制血管内皮细胞生长中的作用 癌前病变向肿瘤的进展将被研究。最后，在Aim4中，我们将建立FGFR2， PFGFR2和pS6作为CSCC和肿瘤侵袭性的预测标记物以及作为潜在的靶点 口腔鳞癌的治疗。我们还将评估其在抑制患者来源的异种移植物生长方面的效果。这个 最终目的是为了了解FGFR和选择性的FGFR2在UVB诱导中的作用 皮肤癌，这将导致靶向药物的发展，可以预防和治疗CSCC。

Cutaneous squamous cell cancer (cSCC) is one of the most rapidly increasing cancers in the USA striking 200,000 Americans annually. Exposure to Solar UVB (ultraviolet B) radiation is the primary etiologic factor for skin cancer. In organ transplant patients there is a 65–100 fold increased incidence of cSCC compared to the general population. Targeted agents have been identified in other common skin cancers such as basal cell carcinoma and melanoma but not for cSCC. Thus, novel mechanism-based targeted approaches are needed for both prevention and treatment of aggressive cSCC. Further, excision of cSCC of the head & neck results in significant facial disfigurement and thus chemoprevention for patients with condemned skin is critical. In our preliminary studies, systemic administration and topical application of fibroblast growth factor receptor (FGFR) inhibitor AZD4547 significantly decreased UVB-induced epidermal hyperplasia and hyper proliferation in SKH- 1 mice. Further, inhibition of FGFR was associated with downregulation of the mTOR and AKT signaling pathway. AZD4547 also inhibited cSCC cell survival, migration and motility that translated into decrease tumor growth in an in vivo xenograft model. Interestingly, deletion of FGFR receptor subtype; FGFR2 significantly decreased mTOR and AKT signaling in cSCC cells suggesting an important role of FGFR2 in AZD4547-mediated effects. Prior published studies demonsrtated a protective role of FGFR2b in the skin. However, it is important to understand that the role of FGFR2b in the skin is highly context dependent and critical experiments are needed to clearly identify its role in the pathogenesis of UVB-induced skin cancer. Based on our preliminary data, our central hypothesis is targeting FGFR and selectively FGFR2 is critical for prevention of cSCC. Accordingly, in Aim1, we will determine temporal effects of AZD4547 on UVB-induced acute epidermal hyperplasia and hyper proliferation. In addition, we will also assess the effects of AZD4547 on UVB-induced tumor promotion and progression. Aim2 will determine the time course for UVB-induced FGFR activation and assess the effect of FGFR inhibition on downstream FGFR signaling. Using K14.CreERT2 x FGFR2bflox/flox mice, the role of FGFR2b in modulating UVB-induced mTORC1 and AKT activation will also be assessed. In addition, the source and type of FGFR2 ligands-induced by UVB in the skin will also be studied. Aim3 will primarily focus on establishing the role of FGFR2 in UVB-induced epidermal hyperplasia, apoptosis and skin carcinogenesis. Further, the role of FGFR2 in inhibiting the progression of premalignant lesions to tumors will be studied. Finally, in Aim4, we will establish FGFR2, pFGFR2 and pS6 as predictive markers for cSCC and tumor aggressiveness and as a potential target for treatment of cSCC. We will also evaluate its efficacy in inhibiting growth of Patient-Derived Xenografts. The ultimate goal is to provide an understanding for the role of FGFR and selectively FGFR2 in UVB-induced skin cancer which will lead to development of targeted agents that could prevent and treat cSCC.