Abstract
摘要:蕾莎瓦(sorafenib)是最早被核准用於治療晚期肝癌的小分子標靶藥物,它可以同時抑制腫瘤的血管生成和增殖,有效延緩腫瘤惡化的速度,並延長病人存活。然而,起初受sorafenib控制的腫瘤,在平均6個月治療後,會逐漸產生對sorafenib的抗藥性。因此侷限的sorafenib的治療效果。了解肝癌細胞對sorafenib產生抗藥性的原因,進一步發展預測抗藥性的方法,是改善肝癌治療效果的重要議題。 Sorafenib要發揮抑制肝癌的效果,必須經由細胞表面的傳送子(transporter)將藥物送進細胞,其中organic anion transporter peptides 8 (OATP8) 是將sorafenib送入肝癌細胞最重要的傳送子。根據我們的實驗結果,在對sorafenib產生後天抗藥性的三種肝癌細胞株中,皆可見OATP8的表現量在治療過程中逐漸減少;OATP8的表現量會決定sorafenib進入肝癌細胞內的速率,進而影響該細胞株對sorafenib的反應。因此,我們認為肝癌細胞的OATP8表現量,可用於預測sorafenib治療後所產生的後天抗藥性。 OATP8傳送子不僅與sorafenib進入細胞的量有關,它也參與了核磁共振造影顯影劑Gd-EOB-DTPA (Primovist®)被肝細胞吸收的過程。OATP8表現量低的肝腫瘤,在Gd-EOB-DTPA-enhanced MRI(EOB-MRI)的肝膽相(hepatobiliary phase)有較低的顯影,因此我們推論:肝癌細胞表面的傳送子缺乏或異常,是造成sorafenib抗藥性的重要原因,這些有抗藥性的腫瘤,在EOB-MRI的肝膽相,應該呈現較低度的顯影。我們可以利用這個機制,以非侵入性的影像方法,預測肝癌在sorafenib治療過程中對sorafenib產生的抗藥性。 為了證實以上假說,本前瞻性研究計畫,將收集75個肝癌病人,在接受sorafenib治療前,及治療過程中,定期以EOB-MRI追蹤目標腫瘤的大小、數量,及EOB-MRI肝膽相的顯影強度,探討肝癌病人在產生sorafenib後天抗藥性的過程中,EOB-MRI影像特徵與傳送子表現量和抗藥性的關聯;以及這些影像特徵變化對病人癒後的影響,藉此發展可以預測藥物療效的影像標記。
Abstract: Until now, sorafenib (NexavarR) is the first approved systemic therapy shown to significantly improve overall survival and delay the time to progression in patients with advanced hepatocellular carcinoma (HCC). In selected patients, it can also work as a combination therapy with transarterial chemoembolization (TACE), or an adjuvant therapy after HCC resection. However, acquired resistance frequently usually develop within 6 months after starting treatment and results in poor long-term survival. To improve treatment outcome, it is important to look for markers of acquired resistance during sorafenib treatment, and find ways to reduce the resistance. To exhibit its anticancer activities, sorafenib has to enter the tumor cells with the help of transporters on the cell membrane. In some human cancers, lower expression levels of the transporters has been reported to correlate with the drug resistance. Organic anion transporting polypeptide 8 (OATP8) is the most important transporter in the hepatic uptake of sorafenib. Our previous data showed that OATP8 expression is significantly lost in acquired sorafenib resistant HCC cell lines (P<0.0001). The OATP8 expression determines the intracellular concentrations of sorafenib and consequently influences drug sensitivity. OATP8 is a potential predicting factor for the development of acquired sorafenib resistance in HCC. OATP8 is also a major uptake transporter involved in the metabolism of gadoxetic acid (Gd-EOB-DTPA), which is a hepatobiliary-specific contrast medium for MRI. Significant correlation has been found between the expression level of OATP-8 and the signal intensity in the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI (EOB-MRI). Decreased signal intensity has been found in hepatic tumors with lower expression level of OATP-8. We hypothesis the changes of enhancing pattern of EOB-MRI can predict the development of sorafenib resistance in HCC during sorafenib treatment. Rapid decrease of signal intensity in the hepatobiliary phase of EOB-MRI is correlate with the poor outcome of HCC. In this study, we are going to perform a prospective study that included 75 consecutively enrolled advanced HCC patients who underwent EOB-MRI examination before and after sorafenib treatment alone. By this study, we aim to elucidate the correlation of EOB-MRI enhancing pattern, OATP8 expression level and acquired resistance to sorafenib. Furthermore, we will evaluate EOB-MRI signal changes in patients with HCC undergoing sorafenib treatment and correlate with clinical outcome.
Keyword(s)
肝細胞癌
蕾莎瓦
OATP8傳送子
抗藥性
動態對比顯影磁振造影
hepatocellular carcinoma
sorafenib
Organic anion transporting polypeptide 8 transporter
resistance
dynamic contrast-enhanced magnetic resonance imaging