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）辐射是主要的致病因素， 皮肤癌在器官移植患者中，cSCC的发病率是正常人的65-100倍。 一般人口。靶向药物已在其他常见的皮肤癌，如基底细胞癌， 癌和黑色素瘤，但不适用于cSCC。因此，需要新的基于机制的靶向方法 预防和治疗侵袭性cSCC。此外，头部和颈部的cSCC的切除导致 严重的面部毁容，因此，对皮肤受损的患者进行化学预防是至关重要的。在我们 成纤维细胞生长因子受体（FGFR）的初步研究、全身给药和局部应用 抑制剂AZD 4547可显著降低UVB诱导的SKH- 1只小鼠。此外，FGFR的抑制与mTOR和AKT信号转导的下调有关。 通路AZD 4547还可抑制cSCC细胞的存活、迁移和运动，从而降低肿瘤生长。 在体内异种移植模型中的生长。有趣的是，FGFR受体亚型的缺失; FGFR 2显著地 cSCC细胞中mTOR和AKT信号传导减少，表明FGFR 2在 AZD 4547介导的效应。先前发表的研究证明了FGFR 2b在皮肤中的保护作用。 然而，重要的是要理解FGFR 2b在皮肤中的作用是高度依赖于环境的 并且需要关键的实验来明确其在UVB诱导的皮肤癌的发病机制中的作用。 根据我们的初步数据，我们的中心假设是靶向FGFR，选择性地FGFR 2是 对于预防CSCC至关重要。因此，在Aim 1中，我们将确定AZD 4547对 UVB诱导的急性表皮增生和过度增殖。此外，我们亦会评估 AZD 4547对UVB诱导的肿瘤促进和进展的影响。Aim 2将决定 本发明的目的是检测UVB诱导的FGFR活化并评估FGFR抑制对下游FGFR信号传导的影响。 使用K14.CreERT2 x FGFR 2bflox/flox小鼠，研究了FGFR 2b在调节UVB诱导的mTORC 1和 还将评估AKT激活。此外，UVB诱导的FGFR 2配体的来源和类型也与UVB诱导的FGFR 2配体的来源和类型有关。 皮肤也将被研究。Aim 3将主要集中于确定FGFR 2在UVB诱导的细胞凋亡中的作用。 表皮增生、细胞凋亡和皮肤癌变。此外，FGFR 2在抑制肿瘤细胞增殖中的作用也被证实。 将研究癌前病变到肿瘤的进展。最后，在目标4中，我们将建立FGFR 2， pFGFR 2和pS 6作为cSCC和肿瘤侵袭性的预测标志物，以及作为治疗的潜在靶点 CSCC的治疗我们还将评价其抑制患者来源异种移植物生长的有效性。的 最终目的是了解FGFR和选择性FGFR 2在UVB诱导的细胞凋亡中的作用。 皮肤癌，这将导致开发可以预防和治疗cSCC的靶向药物。

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.