探索增強 IDH1 突變型肝內膽管癌的化學治療敏感度之策略

Abstract

肝內膽管癌(Intrahepatic cholangiocarcinoma，iCCA)是一種源自膽管上皮細 胞的惡性腫瘤，其發生率逐年攀升。由於缺乏有效的早期診斷工具，患者多在晚期 才被確診。目前，臨床治療以手術為主，輔以 GemCis(gemcitabine 和 cisplatin) 聯合化療。然而，治療效果有限，生存率仍不理想。針對異檸檬酸脫氫酶 I 型(isocitrate dehydrogenase1，IDH1)突變型 iCCA 的標靶藥物 ivosidenib 已獲美國食品藥物 管理局(FDA)核准，其機制為抑制突變型 IDH1，減少致癌代謝物 2-羥基戊二酸 (D-2-hydroxyglutarate，D-2HG)的生成，從而阻止癌化進程。然而，臨床數據顯 示其療效仍有進一步提升的空間。 近年研究發現，D-2HG 在癌細胞中具有雙重作用:一方面促進癌化，另一方 面則透過抑制 DNA 修復或增加活性氧(reactive oxygen species，ROS)的生成， 使癌細胞更易受到損傷。基於此，本研究提出結合 α-酮戊二酸(α-ketoglutarate) 與化療藥物的協同治療策略。α-酮戊二酸可提升癌細胞內 D-2HG 含量，進一步增 加癌細胞的脆弱性(cell vulnerability)，從而增強其對化療藥物的敏感性，最終達 到有效殺傷腫瘤細胞的目標。

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive form of liver cancer with a rising global incidence and significant challenges in early diagnosis. The current standard treatment involves surgical resection, often complemented by combination chemotherapy (GemCis). In recent years, targeted therapies such as ivosidenib (IVO) have been developed to address specific molecular subtypes of iCCA, including mutant isocitrate dehydrogenase 1 (mIDH1). IVO, an FDA-approved agent, inhibits mIDH1 to reduce levels of the oncometabolite D-2-hydroxyglutarate (D-2HG), thereby suppressing tumorigenesis. Despite its initial promise, clinical data reveal limited response rates and the emergence of drug resistance with prolonged use. Recent findings highlight the dual role of D-2HG, which not only promotes tumorigenesis but also sensitizes cancer cells by impairing DNA repair mechanisms or elevating reactive oxygen species (ROS) levels. Building on this concept, our study aims to enhance intracellular D-2HG levels through α-ketoglutarate supplementation, thus increasing cancer cell vulnerability and improving their sensitivity to chemotherapy. This innovative approach seeks to achieve a synergistic therapeutic effect, offering a promising strategy for the treatment of mIDH1 iCCA.