2015-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657137摘要：曱狀腺癌是内分泌系統最常見的癌症。曱狀腺癌因其接受手術及放射碘的治療後， 疾病大多可以得到有效控制。但是在臨床上，仍有許多的病人在復發後，無法以 手術切除，且放射碘也未見療效，此稱為放射碘無效之曱狀腺癌。更有些曱狀腺 癌在一發現即為分化不良的曱狀腺癌(poorly differentiated thyroid carcinoma),或是 未分化癌(anaplastic thyroid carcinoma)。對於傳統的治療，療效不佳，是以尋求新 的藥物治療的需求，對於這樣的疾病來說，是非常迫切需要的。傳統曱狀腺癌樂物的研究，基本上是以癌症細胞株進行細胞實驗及動物模式的實 驗。細胞株的實驗因其性狀及基因的改變，與原生的曱狀腺癌細胞不同。當然， 以細胞株為基礎進行的實驗結果，也常無法在人體上得到一樣的療效。本實驗所要建立的動物實驗模式，是以病人身上取得的曱狀腺癌腫瘤小塊，直接 種入免疫不全的小鼠體内，在動物身上培養。這樣的動物模式應較傳統細胞株研 究更接近病人體内的真實的反應。在第一年，將建立癌症腫瘤在小鼠體内培養平 台，並比對病人腫瘤組織檢體與動物模式中的腫瘤檢體之相似度。第二年，將對 腫瘤植入小鼠，以現行治療病人的化學治療藥物進行治療。並比較治療後腫瘤大 小的變化與臨床上病人接受治療的反應，在後期則可以考慮先以小鼠研究腫瘤對 於藥物的反應，並作為治療病人的建議。第三年，將進行治療之機轉研究，在病 人曱狀腺癌組織檢體進行基因微陣列(DNA M icroarray)的研究並與治療的結果 比對，可知何種基因表現形的腫瘤對於何種治療可以有較好的療效。<br> Abstract: Thyroid cancer is the most common endocrine cancer. The incidence of thyroid cancer is increasing in the recent decades. In Taiwan, it ranked the 6th among female malignancy. Most of the thyroid cancer can be controlled by surgery alone or with radioiodine. But treatment for radioiodine refractory cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer remained to be developed. Anaplastic thyroid cancer is one of the most lethal human malignancies, and is associated with a median survival of less than six months after diagnosis. A number of different treatment modalities, including external beam radiotherapy,chemotherapy(Paclitaxel, Carboplatin, Cisplatin) and more recently, tyrosine kinase inhibitors such as sunitinib, sorafenib, and pazopanib, have been used, but have had limited efficacy. Thyroid cancers hold molecular alterations such as BRAF mutations, HRAS mutations, and PIK3CA mutations. Nevertheless, the association between know molecular alterations and effective targeted therapies is not clear. To identify and validate molecular drug targets is therefore important in searching for novel therapeutic modalities for advanced thyroid cancers.Cell lines and cell line-derived xenograft models are most widely used for validation of treatment efficacy. However, it is well known that in vivo models are prone to culture-induced genotypic and phenotypic alteration. Thus, the extrapolation of in vitro results to clinical treatment is questionable. Heterotransplantation of fresh human cancer tissue, i.e.tumorgraft may more accurately recapitulate the primary patient tumor. When maintained under conditions of low passage in vivo, they may maintain histologic and genomic fidelity. Such model will be useful in predicting treatment response both in chemotherapy and in novel drug discovery.In the first year, we would develop this tumorgraft mouse model and validate the similarity between the specimens of original tumors with this tumorgrafts after low passage condition.In the second year, we would use conventional chemotherapy agents that would be used in the patients of tumor donor. Then we could compare the treatment response between original tumors and the experimental tumorgrafts. In the end of the 2nd year, we could use this model to test multiple different agents in the mouse model before we treat this patient. Hence, the information obtained from mouse model could guide the treatment selection for patients.In the third year, we would use DNA microarray to test specimens, then supervised by treatment response. Doing this, we could identify treatment responsive genotype, then further understand the possible new treatment to treat the refractory subtype.