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研究生：	張光裕 Chang, Kwang-Yu
論文名稱：	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 Investigation of EGFR/PI3K/AKT/mTOR pathway for its role in oral cancer and development of the potential treatment strategy
指導教授：	張俊彥 Chang, Jang-Yang 呂佩融 Lu, Pei-Jung
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	91
中文關鍵詞：	上皮增生因子受體、磷酸肌醇3激酶、AKT 、哺乳動物雷帕黴素蛋白、磷酸酶及張力蛋白同源物、BGT226 、口腔癌
外文關鍵詞：	epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN), BGT226, oral cancer
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儘管多專科整合治療的策略在現今有效地改善口腔癌患者的預後，然而對於嚴重晚期疾病的病人其治療效果卻仍然是有限的。從現今治療頭頸部腫瘤的臨床經驗中可知，作為在腫瘤發展期間的關鍵因子，表皮生長因子受體（EGFR）因此成為生物治療藥劑的目標蛋白質。此生物治療藥劑的成功發展鼓舞了我們研究其他細胞訊息傳遞的路線是否也有值得發展的潛在目標。從以往的報導可知，口腔癌和其他的頭頸部癌症也依賴於激活磷酸肌醇3激酶（PI3K）/AKT /哺乳動物雷帕黴素（mTOR）的訊號傳遞。而此訊號傳遞鏈亦為EGFR信號傳導網路中的一個下游分支。因此我們首先安排研究，以評估調控此傳遞鏈的上游因子是否有基因或蛋白質的表現缺失。一開始我們在所收集的的108個檔案組織切片中發現高比例的磷酸化AKT（pAKT）被表現出來。藉由這些被激活的途徑，促使我們研究上游調控的因子，如EGFR，PI3K，和磷酸酶及張力蛋白同源物（PTEN）。研究結果發現無論是野生型和第三變異型的EGFR，以及PTEN方面，皆普遍都有明顯的變異或失控的表現。進一步的檢視發現第三變異型的EGFR與腫瘤分期具有相關聯性。後續的統計分析表示，pAKT和與第三變異型的EGFR、以及腫瘤分期是決定患者的生存期重要因子。這些在口腔癌臨床檢體的調查結果證實此傳導路徑被演了一個重要的角色，並因此假設透過阻斷此路徑應為具有潛能的治療策略。因此我們採用了一種新的小分子化合物，NVP-BGT226（BGT226），作為在實驗室中研究同時直接抑制PI3K和哺乳動物雷帕黴素靶蛋白（mTOR）時對於腫瘤細胞的影響。隨著化合物的施加，所有細胞系的生長皆在毫微莫爾濃度的範圍內有效地被抑制。路徑訊息的研究顯示PI3K/AKT/mTOR的相關激活訊息被BGT226有效抑制。細胞週期分析則顯示處於G0/G1的細胞增加，同時伴隨處於S期的細胞減少，皆表示細胞增長的能力被減緩。而進一步針對細胞死亡的分析顯示，經由BGT226處理的細胞並不表現凋亡，也就是第一型程序性細胞死亡。相對的，自噬現象的分析證明細胞呈現出第二型細胞程序性的特徵，包括自噬體檢測量的增加以及自噬性溶酶體過程的表現。總結來說，BGT226對細胞的影響包括產生自噬作用以及與其相關的細胞死亡。在生物體的實驗發現，餵食BGT226的移植瘤小鼠在實驗期間會使腫瘤生長速度趨緩，並也觀察到在實驗組無明顯副作用的產生。基於這些結果可歸納出針對PI3K/AKT/mTOR訊息傳導路徑的抑制策略是值得轉譯於人類的研究上。因此我們將在未來發起一個單臂兩階段的第二期臨床試驗以抑製此路徑的專一藥劑使用於口腔和其他的頭頸部癌症病人。

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.

Table of Contents
Abstract in Chinese	III
Abstract in English	V
Acknowledgement	VII
Abbreviations	VIII~IX
Table of Contents	X~XI
Table Contents	XII
Figure Contents	XIII~XIV
Chapter One: Introduction	1~10
1.1	Introduction to the oral cancer	2
1.2 	Identifiction of the crucial signaling pathway contributes to drug development	3
1.2.1 	The epidermal growth factor receptor pathway in HNC 4
1.2.2 	The phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) cascade in HNC	4
1.3 	Distinguished molecular characteristics in oral cancer is the major pitfall which impedes clinical development of the targeting agents	5
1.3.1 	Complexicity of EGFR targeting strategy in head and neck cancer	6
1.3.2 	Turbulance of the activated PI3K-AKT-mTOR	7
1.4 	It is urgency for development of novel drug in the treatment of oral cancer	8
1.4.1 	PI3K-AKT-mTOR pathway is candidate target for the treatment of oral cancer	8
1.5 	The goal and the specific aims	9
Chapter Two: Dissecting the EGFR-PI3K-AKT Pathway in Oral Cancer Highlights the Role of the EGFR Variant III and its Clinical Relevance 	11~32
2.1	Abstract	12
2.2	Introduction	13
2.3	Materials and methods	14
2.4	Result	18
2.5	Discussion	21
2.6	Figure and tables	23
Chapter Three: Novel PI3K/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibotry Activity Against Human Head and Neck Cancer Cells in vitro and in vivo	33~66
3.1	Abstract	34
3.2	Introduction	35
3.3	Materials and methods	36
3.4	Result	42
3.5	Discussion	46
3.6	Figures and tables	50
Chapter Four: General Discussion and the Future Plan	67~75
4.1	Experimental findings	68
4.2	Exploration of EGFRvIII and its indispensible role in oral cancer	68
4.3	Consideration of the alterative pathway such as IL6-STAT3 in oral cancer	69
4.4	Elucidation of PI3K-AKT-mTOR pathway in the cetuximab treatment	69
4.5	Potential synergistic effect by PI3K inhibition and radiation	70
4.6	Clinical trial for translation of the PI3K/mTOR inhibitory strategy in patients	71
4.7	Conclusion	71
4.8	Figures	72
Chapter Five: References	76~86
Appendix: Curriculum Vitae	87~91
 
Table Contents
Table 2.1	Demography of patients characteristic (N=108)	30
Table 2.2	Association analyses of EGFRvIII expressing status with the other 	factors	31
Table 2.3	Univariate and multivariate analyses for the overall survival	32
Table 3.1	The IC50 of growth inhibition assay using BGT226 or cisplatin in various head and neck cancer cell lines	66
 
Figure Contents
Figure 1.1	The anatomy structure of the upper aerodigestive tract	3
Figure 1.2	Mechanism of anti-EGFR inhibitors	4
Figure 1.3	Schema of regulatory route in PI3K-AKT-mTOR signaling pathway	5
Figure 1.4	Frequent mutations leading to structural or functional alterations of EGFR which may potentially lead to aberrant signaling of the receptor	7
Figure 1.5	Schema of the dual PI3K/mTOR inhibitors and their target in the pathway	9.
Figure 1.6	Schema of the study airs and the goal of the drug development	10
Figure 2.1 	Schema of the PI3K-AKT-mTOR pathway and EGFR protein as the regulatory factor	23
Figure 2.2	Protein detection of EGFR and EGFRvIII by specific antibodies	24
Figure 2.3 	Survival curves according to TNM stage	25
Figure 2.4 	Immunohistochemical staining of the tumor tissue	26
Figure 2.5 	Gene copy numbers of the samples	27
Figure 2.6 	The impact of pAKT and EGFRvIII on patient survival	28
Figure 3.1	A hypothesized model for BGT226 to inhibit PI3K-AKT-mTOR pathway.	50
Figure 3.2 	Diverse protein and gene copy number expression was noted in all cell lines	51
Figure 3.3	Effect of BGT226 on intracellular signal changes in head and neck cancer cell lines	52
Figure 3.4 	Effect of the cell growth and the intracellular signals by BGT226 and the other PI3K or mTOR inhibitors	54
Figure 3.5 	Effect of BGT226 on cell cycle	55
Figure 3.6 	Minimal fragmented DNA was observed in BGT226-treated FaDu cells	56
Figure 3.7	Lacking of the activated caspase 3 and PARP in BGT226-treated cells	57
Figure 3.8 	Analysis of autophagy in BGT226-treated cell lines	58
Figure 3.9 	Cell death of FaDu cells treated with BGT226 was associated to autophagy	60
Figure 3.10	Xenograft model of FaDu cells	62
Figure 3.11	Attenuation of PI3K-AKT-mTOR associated route and autophagyin the BGT226 fed mouse	63
Figure 3.12	The role of specific lysosomal and cytosolic proteases in the BGT226-treated FaDu cells	64
Figure 3.13	Ex vivo test of human lymphocytes showed BGT226 did not alter its viability	65
Figure 4.1	Immunohistochemical staining of STAT3 and IL6.	72
Figure 4.2 	Study applying the cetuximab resistant cell lines	73
Figure 4.3	Synergestic anti-tumoral effect by the combination treatment of BGT226 with radiation in FaDu cells	74
Figure 4.4	Schema of a proposed phase II clinical trial for the assessment of BGT226 in HNC	75 
                                    

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