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

靶向成纤维细胞生长因子受体-2b 预防和治疗皮肤鳞状细胞癌。

基本信息

批准号：
10318934
负责人：
John DiGiovanni
金额：
$ 38.32万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318934
关键词：
AKT Signaling Pathway Acute American Apoptosis Basal cell carcinoma Biological Markers Cancer cell line Cell Proliferation Cell Survival Chemoprevention Chemopreventive Agent Chronic Clinical Cre lox recombination system Cutaneous Data Development Diagnosis Down-Regulation Epidermis Etiology Evaluation Excision Exposure to FGF10 gene FGF2 gene FGF7 gene FGFR1 gene FGFR2 gene FRAP1 gene Family member Fibroblast Growth Factor Receptors General Population Goals Growth Head and Neck Squamous Cell Carcinoma Hyperplasia In Vitro Incidence Lesion Ligands Louisiana MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Malignant Squamous Cell Neoplasm Mediating Modeling Morbidity - disease rate Mus Neck Cancer Neoplasm Metastasis Organ Transplantation Ozone PECAM1 gene Pathogenesis Pathologic Patients Phosphorylation Play Population Prevention Proto-Oncogene Proteins c-akt Publishing Receptor Activation Receptor Inhibition Receptor Signaling Retrospective Studies Risk Role Signal Pathway Signal Transduction Skin Skin Cancer Skin Carcinogenesis Skin Neoplasms Solar Energy Source Stains Testing Therapeutic Time Tissues Topical application Translating Transplant Recipients Tumor Markers Tumor Promotion Tumor Volume UV induced UVB induced Ultraviolet B Radiation Ultraviolet Rays Xenograft Model angiogenesis base cancer cell cancer prevention carcinogenesis cell motility cellular imaging experimental study facial disfigurement fibroblast growth factor receptor 2b imaging system in vivo inhibitor keratinocyte mTOR Signaling Pathway melanoma migration mortality mouse model novel patient derived xenograft model potential biomarker predicting response predictive marker premalignant prevent receptor skin lesion skin squamous cell carcinoma tanning booths targeted agent translational potential tumor tumor growth tumor progression tumor registry tumor xenograft ultraviolet

项目摘要

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.

皮肤鳞状细胞癌 (cSCC) 是美国增长最快的癌症之一每年有 200,000 美国人暴露于太阳 UVB（紫外线 B）辐射是导致该病的主要原因。与移植器官患者相比，皮肤癌的发生率增加 65-100 倍。已在其他常见皮肤癌（例如基底细胞癌）中发现了靶向药物。因此，需要新的基于机制的靶向方法。用于预防和治疗侵袭性鳞状细胞癌此外，切除头颈部鳞状细胞癌会导致严重的面部畸形，因此对皮肤受损的患者进行化学预防至关重要。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 AZD4547 显着降低 SKH 中 UVB 诱导的表皮增生和过度增殖此外，FGFR 的抑制与 mTOR 和 AKT 信号传导的下调有关。 AZD4547 还抑制 cSCC 细胞的存活、迁移和运动，从而减少肿瘤。体内异种移植模型中的生长表明，FGFR2 受体亚型显着缺失； cSCC 细胞中 mTOR 和 AKT 信号传导减少，表明 FGFR2 在 AZD4547 介导的作用。先前发表的研究证明了 FGFR2b 对皮肤的保护作用。然而，重要的是要了解 FGFR2b 在皮肤中的作用高度依赖于环境需要进行关键实验来明确其在 UVB 诱发的皮肤癌发病机制中的作用。根据我们的初步数据，我们的中心假设是以 FGFR 为目标，并且选择性地 FGFR2 因此，在目标 1 中，我们将确定 AZD4547 对预防 cSCC 的时间影响。此外，我们还将评估 UVB 引起的急性表皮增生和过度增殖的影响。 AZD4547 对 UVB 诱导的肿瘤促进和进展的作用将决定 Aim2 的时间进程。 UVB 诱导 FGFR 激活并评估 FGFR 抑制对下游 FGFR 信号传导的影响。使用 K14.CreERT2 x FGFR2bflox/flox 小鼠，FGFR2b 在调节 UVB 诱导的 mTORC1 和此外，还将评估 UVB 诱导的 FGFR2 配体的来源和类型。 Aim3 还将主要研究皮肤中 FGFR2 在 UVB 诱导中的作用。进一步研究FGFR2在抑制表皮增生、细胞凋亡和皮肤癌发生中的作用。最后，在Aim4中，我们将研究FGFR2， pFGFR2 和 pS6 作为 cSCC 和肿瘤侵袭性的预测标志物，并作为潜在靶标我们还将评估其抑制患者来源异种移植物生长的功效。最终目标是了解 FGFR 和选择性 FGFR2 在 UVB 诱导中的作用皮肤癌，这将导致开发可以预防和治疗鳞状细胞癌的靶向药物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Clarion Call of the COVID-19 Pandemic: How Medical Education Can Mitigate Racial and Ethnic Disparities.

COVID-19 大流行的号角：医学教育如何减轻种族和民族差异。

DOI：
发表时间：
2021-11-01
期刊：
影响因子：
0
作者：
Prince, Andrew D P;Green, Alexander R;Brown, David J;Thompson, Dana M;Neblett Jr, Enrique W;Nathan, Cherie;Carethers, John M;Gee, Rebekah E;Gruppen, Larry D;Mangrulkar, Rajesh S;Brenner, Michael J
通讯作者：
Brenner, Michael J

Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis

抑制成纤维细胞生长因子受体可减轻 UVB 诱导的皮肤癌发生

DOI：
发表时间：
1970-01-01
期刊：
影响因子：
0
作者：
Megha A. Thakur;Alok R. Kh;elwal;elwal;X. Gu;O. Rho;S. Carbajal;Rima A. K;ula;ula;J. DiGiovanni;C. Nathan
通讯作者：
C. Nathan

Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma.

成纤维细胞生长因子受体促进皮肤鳞状细胞癌的进展。

DOI：
发表时间：
2019
期刊：
影响因子：
4.6
作者：
Khandelwal, Alok R;Kent, Burton;Hillary, Savage;Alam, Md Maksudul;Ma, Xiaohua;Gu, Xin;DiGiovanni, John;Nathan, Cherie
通讯作者：
Nathan, Cherie