Principal Investigator

Cherie-Ann O
Nathan
Awardee Organization

Louisiana State Univ Hsc Shreveport
United States

Fiscal Year
2022
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

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

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 SKH1 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.

Publications

  • Thakur MA, Khandelwal AR, Gu X, Rho O, Carbajal S, Kandula RA, DiGiovanni J, Nathan CO. Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis. The Journal of investigative dermatology. 2022 Nov;142(11):2873-2884.e7. Epub 2022 May 10. PMID: 35551922
  • Khandelwal AR, Kent B, Hillary S, Alam MM, Ma X, Gu X, DiGiovanni J, Nathan CO. Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma. Molecular carcinogenesis. 2019 Oct;58(10):1715-1725. Epub 2019 Jun 29. PMID: 31254372
  • Prince ADP, Green AR, Brown DJ, Thompson DM, Neblett EW Jr, Nathan CA, Carethers JM, Gee RE, Gruppen LD, Mangrulkar RS, Brenner MJ. The Clarion Call of the COVID-19 Pandemic: How Medical Education Can Mitigate Racial and Ethnic Disparities. Academic medicine : journal of the Association of American Medical Colleges. 2021 Nov 1;96(11):1518-1523. PMID: 33913439