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Proceedings Paper

Vandetanib sensitises oral squamous cell carcinoma to photodynamic therapy through NHEJ impairment and modulation of tumour microenvironment (Conference Presentation)

Paper Abstract

Despite the advances of therapeutic approaches, morbidity and mortality rate of oral squamous cell carcinoma (OSCC) have not improved significantly during the last 30 years. Photodynamic therapy (PDT) represents a potential treatment modality for locally recurrent OSCC. However, treatment resistance attributed to PDT-induced epidermal growth factor receptor (EGFR) up-regulation was reported. Here, we showed that vandetanib, a multi-target tyrosine kinase inhibitor that inhibits EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2) enhance the efficacy of PDT. First, we observed increased cytotoxicity in the combinatorial treatment that is attributed to impaired DNA double strand break (DSB) repair. We revealed significant down-regulation DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression to be the downstream target following inhibition of nuclear EGFR accumulation, therefore impairing non-homologous end-joining (NHEJ) following PDT. Next, the combinatorial treatment-mediated tumour vasculature shutdown and normalisation, coupled with reduction of PDT-induced EGFR activation corresponded to the most pronounced tumour growth delay in vivo. Interestingly, we observed the restoration of tumour cell proliferation and vascularisation, coupled with ERK1/2 activation in the recurrent tumours post-vandetanib+PDT treatment. This corroborated the importance of the modulation of the tumour microenvironment for the observed synergistic efficacy of vandetanib+PDT combinatorial treatment. Collectively, our data suggests that vandetanib works synergistically with PDT through the impairment of EGFR-dependent DNA repair machinery and modulation of tumour microenvironment.

Paper Details

Date Published: 14 August 2019
Proc. SPIE 11070, 17th International Photodynamic Association World Congress, 1107038 (14 August 2019); doi: 10.1117/12.2527990
Show Author Affiliations
Pek Lim Chu, Duke-NUS Graduate Medical School (Singapore)
Waseem A. Shihabudeen, National Cancer Ctr. of Singapore (Singapore)
Kar Perng Low, National Cancer Ctr. of Singapore (Singapore)
Dennis J.J. Poon, National Cancer Ctr. of Singapore (Singapore)
Bhuvaneswari Ramaswamy, National Cancer Ctr. of Singapore (Singapore)
Zhong-Guo Liang Jr., Guangxi Medical Univ. (China)
Wen Long Nei, National Cancer Ctr. of Singapore (Singapore)
Kevin L.M. Chua, National Cancer Ctr. of Singapore (Singapore)
Patricia S.P. Thong, National Cancer Ctr. of Singapore (Singapore)
Khee Chee Soo, National Cancer Ctr. of Singapore (Singapore)
Eugenia L.L. Yeo, Duke-NUS Graduate Medical School (Singapore)
Melvin L.K. Chua, Duke-NUS Graduate Medical School (Singapore)
National Cancer Ctr. of Singapore (Singapore)

Published in SPIE Proceedings Vol. 11070:
17th International Photodynamic Association World Congress
Tayyaba Hasan, Editor(s)

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