2021-09-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/669453"攝護腺癌於美國癌症統計發生率為第一名、死亡率第二名在台灣都為第五名，當癌症轉移時，病人五年存活只剩三成。賀爾蒙治療為臨床上第一線採用的治療方式，然而有一部分的病人在治療後的二到三年間，會演變成抗藥性攝護腺癌，這種致命性腫瘤導致癌症患者不良的癒後，並成為臨床診斷與治療中的關鍵問題。進一步探究原因可能為，腫瘤能夠透過改變微環境並重塑宿主器官內的平衡，整個腫瘤生態系的形成也許癌症的惡化或是抗藥性息息相關。為了瞭解治療後復發的攝護腺癌是如何去改變代謝環境進而重塑腫瘤生態系，我們的研究中發現在恩雜魯胺 (Enzalutamide) 治療後產生抗藥性的攝護腺癌細胞其長碳鏈脂肪酸含量明顯提高，也能發現與脂肪相關的酵素表現也是增加，此結果，在抗藥性細胞株、臨床病人組織以及病人數據庫中亦可發相似結果。延長酶主要是負責脂肪酸延長相關功能的酵素，我們發現其的表現量 （延長酶亞型二，四以及七）在抗藥性與較惡性的攝護腺癌明顯增高，代表著長碳鏈脂質代謝與攝護腺癌的惡化有關。進一步研究中發現，降低細胞內延伸酶的表現量或是降低脂質含量能夠提升對恩雜魯胺 (Enzalutamide) 對於抗性攝護腺癌細胞的毒殺能力，進而增加治療效果。在動物實驗中，我們也能發現在敲除延長酶亞型二號的腫瘤生長會變慢，在恩雜魯安結合降低體內脂肪藥物的合併治療中，明顯的將腫瘤抑制，然而長碳鏈脂防是如何造成抗性的分子機制仍不清楚。另一方面，在過去研究已發現攝護腺癌腫瘤治療過程會誘導基因多倍體與多倍體巨細胞的出現，此多倍體細胞會表達高量致癌基因進而產生抗藥性以及轉移能力，這些基因也包含了與代謝相關途徑，暗示著這過程與攝護腺病人惡化與治療效果息息相關。因此我們假設治療造成的多倍體現象可能與長碳鏈酵素表現量有關，在我們的實驗結果中顯示基因體多倍體的出現與癌症基因高表現呈現正相關性。然而，在攝護腺癌惡化過程脂質代謝與基因體不穩定性之間的關聯性與分子機制仍然不清楚。此計畫目的，將會探討脂質代謝於抗藥性攝護腺癌與多倍體巨細胞的調控機制，並進一步了解是否基因體的不穩定性會參與其中並調控細胞代謝體的改變，以及基於此機制找尋治療型抑制劑與標靶藥物合併對於攝護腺癌病人的合併治療可行性。 未來兩年預計執行目標: Aim1: 探討長碳鏈脂質代謝對攝護腺細胞惡化影響 Aim2: 探討致癌基因對於脂質代謝改變的分子機制以及合併治療可行性 Aim3: 探討治療誘發染色體不穩定與致癌基因及脂質代謝改變關係 Aim4: 尋找潛力小分子藥物以及臨床試驗前期合併治療效果" "Prostate cancer (PC) is one of the most diagnosed cancers and has an arising rate of mortality in the USA and Taiwan. Androgen deprivation therapy (ADT) has been the standard treatment for advanced PCa. However, castration resistant PC (CRPC) occurs within 1-2 years of initiation of ADT, which is related to poor survival. Hence, prevention of cancer progression and development of effective treatments have become an imperative issue against the advanced PCa. Previous studies have revealed that CRPC alters multiple factors causing microenvironment remodeling and even changes metabolism to build up an ecosystem in favor of tumor progression. Lipid metabolism has been reported related to PCa progression. In the investigation of the relationship between lipid metabolism and prostate progression, our preliminary results showed that there were dramatically increased levels of C18, C20 and C22 long-chain fatty acids in enzalutamide-resistant PC cells. Furthermore, Elongases (Elovl 2, 4 and 7) were contributed to fatty acid extension and upregulated in resistant PCa cells, malignant PCa tissues and castration resistance prostate cancer (CRPC) patient database. In addition, decrease of Elovels and lipid content could sensitize PCa cells to Enzalutamide treatment effects. Previous studies have revealed that anti-tumor treatments would induce genomic content (polyploidy) and call polyploidy giant cancer cells (PGCCs), which showed resistant and metastatic abilities. Therefore, our preliminary data showed multiple genomic copies was correlated to oncogenes upregulation including fatty acid related genes. However, there is still less known of the correlation of mechanism between lipid metabolism change and genomic instability in CRPC. This study will reveal the role of fatty acid metabolism and oncogene in CRPC, and then we plan to seek the potential inhibitors based on fatty acid suppression and combination therapeutic strategy in prostate cancer patients. These specific aims are therefore proposed to be executed within two years: Aim 1: To determine the long chain fatty acid function of resistance in CRPC cells. (Year 1) Aim 2: To find out candidates that involve in the alteration of long chain fatty acid metabolism as a potential therapeutic target. (Year 1) Aim 3: To investigate the molecular mechanism involved in the treatment-related genomic instability (multiploidy), which leads to alteration of long chain fatty acid metabolism in CRPC cells. (Year 2) Aim 4: To perform the high throughput screening (HTS) for potential lead compounds and pre-clinical studies for the combined effect of novel hormonal agents (NHA). (Year 2)"攝護腺癌抗藥性攝護腺癌長碳鏈脂肪酸長碳鏈脂肪酸脂肪酸代謝基因體不穩定多倍體多倍體巨細胞延長酶鞘氨醇癌症抗藥性Prostate cancerCastration Resistance Prostate CancerCRPClipid metabolismgenomic instabilitypolyploidypolyploid giant cancer cellPGCCElongaseElovl