Germinoma : Histopathology and Imaging Characteristics of Rare Brain Tumors in Siloam Hospital

Abstract

Background: The treatment of betel-nuts related HNSCC in Taiwan is challenging and related to strong inflammation, invasion, and angiogenesis. In our previous studies, betel-nuts related TW2.6(p53 defective mutation, p16 loss, BCL2þ) was resistant to chemotherapies, radiation, and EGFR inhibitors. In addition to PI3K/mTOR dual inhibition, polo-like kinase inhibitor with radiation, CDK4/6 inhibitor, WEE1 inhibitor, ALK/IGF-1R inhibitor, Bcl2 inhibitor, and eribulin, Astragalus polysaccharides, FGFR inhibitor, CDK4/6 inhibitor, & VEGFR2/FGFR/PDGFR or VEGFR2/c-MET/Axl triple blockage could reverse treatment refractoriness, through the inhibition of mesenchymal transformation & PI3K/Akt/mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. DNA damage response is important in HNSCC tumorigenesis and DDR interventions may enhance tumor antigen presentations and immuotherapy. Purpose: We try to find out DDR interventions in betel-nus related HNSCC. Methods: Polo-like kinase inhibitor, WEE1 inhibitor, PARP inhibitor, and ATR inhibitor were tested on TW2.6 to evaluate (1)the in vitro drug sensitivity; (2)synergistic effects with some chemotherapies and target therapies with MTT assay, colon formation assay, flow cytometry, and western blotting. Results: Volasertib, AZD1775, and foretinib(VEGFR/c-MET/Axl triple inhibitor) could reverse TW2.6 resistance to olaparib. AZD1775 was effective on TW2.6 and could also resensitize docetaxel and enhance further eribulin effects. AZD6738 was effective on TW2.6 and caused (1)several mesenchymal differentiation markers(esp. Twist) drop; (2)p70S6K drop but p-AKT increase; (3)prominent PDL1 & mild BMI-1 drop. Conclusions: TW2.6 might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan. TW2.6 resistance to PARP inhibitor could be handled by PLK1, WEE1, or c-MET inhibition. WEE1 inhibitor could reverse docetaxel resistance. Novel ATR inhibitor mechanisms and combinations(with PI3K inhibitor) should be searched.