研究上皮增生因子受體/磷酸肌醇3激酶/AKT/哺乳動物雷帕黴素靶蛋白(EGFR/PI3K/AKT/mTOR)之訊息傳導路徑於口腔癌的重要性以及潛在治療策略的開發

Despite of the recent advances in multi-discipline strategy, the prognosis of late-staged oral cancer (OC) remains poor and new therapeutic agents are needed. From current clinical experience of the head and neck cancer (HNC) , epidermal growth factor receptor (EGFR) possess crucial role which is then used as a target for biological treatment. The successful development of the strategy inspired us to investigate the other signaling route that showed potential for targeting. It has been reported that OC and the other HNCs also relied on the activation of phosphoinositide 3/kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade, which is a branch of EGFR signaling network. In order to find crucial factors in OC as potential targets for treatment, my study first assessed the aberration of the regulatory factors toward this dysregulated cascade. Initially, high expressing proportion of phosphorylated AKT (pAKT) was found in 108 archival tissues which were surgically resected from OC patients. This finding prompted us to approach the upstream regulators such as EGFR, PI3K, and phosphatase and tensin homolog (PTEN). The results showed prevalent aberrations in EGFR both in the wild-type and the variant III (EGFRvIII) counterpart, as well as in PTEN. Notably, the expression of EGFRvIII was associated to tumor stage. Further statistical analyses indicated pAKT and EGFRvIII as well as tumor stage to be the determinants for the survival of patients. These highlight the aberrant pathway for its potential to be served as a treatment target in the drug development. Based on the findings, we further investigated anti-tumor effect of a novel compound, NVP-BGT226 (BGT226) that directly binds to PI3K and mammalian target of rapamycin (mTOR) simultaneously. With the application of the compound, the growth of all tested cell lines was inhibited efficiently in the range of nanomolar concentration. The studies of the signaling route showed inhibition against activation of the PI3K/AKT/mTOR pathway. Cell cycle analysis revealed an accumulation of cells in the G0/G1 phase with concomitant loss in the S phase, indicating the retarded ability of growth. Further analyses in cell death showed lacking of the type I programmed cell death apoptosis. In contrast, the type II programmed cell death autophagy was significantly detected by the formation of autophagosome and the process of autolysosome. These led to summary that BGT226 induced autophagy and the cell death which was associated to the process. In addition, the in vivo studies using xenograft mouse resulted in a slower growth rate in the experimental group without obvious side effects observed. Based on these data, the specific inhibitory strategy against the PI3K/AKT/mTOR pathway is worthwhile for translation to human study. In conclusion, my study showed the rationale for novel drug development against PI3K/AKT/mTOR pathway in OC, which would be warranted for translation into clinical studies in the future.