請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96946完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 何佳安 | zh_TW |
| dc.contributor.advisor | Ja-an Annie Ho | en |
| dc.contributor.author | 蔡佩臻 | zh_TW |
| dc.contributor.author | Pei-Chen Tsai | en |
| dc.date.accessioned | 2025-02-25T16:10:42Z | - |
| dc.date.available | 2025-02-26 | - |
| dc.date.copyright | 2025-02-25 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-02-05 | - |
| dc.identifier.citation | [1] J.M. Banales, J.J. Marin, A. Lamarca, P.M. Rodrigues, S.A. Khan, L.R. Roberts, V. Cardinale, G. Carpino, J.B. Andersen, C. Braconi (2020) Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 17, 557-588.
[2] S. Tong, J. Wu, Y. Song, W. Fu, Y. Yuan, P. Zhong, Y. Liu, B. Wang (2024) IDH1-mutant metabolite D-2-hydroxyglutarate inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT. Cell Death Discov. 10, 317. [3] R. Dhanasekaran, A.W. Hemming, I. Zendejas, T. George, D.R. Nelson, C. Soldevila-Pico, R.J. Firpi, G. Morelli, V. Clark, R. Cabrera (2013) Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma. Oncol. Rep. 29, 1259-1267. [4] S. Aishima, Y. Oda (2015) Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type. J. Hepato-Biliary-Pancreat. Sci. 22, 94-100. [5] J. Valle, H. Wasan, D.H. Palmer, D. Cunningham, A. Anthoney, A. Maraveyas, S. Madhusudan, T. Iveson, S. Hughes, S.P. Pereira (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273-1281. [6] T. Chung, Y.N. Park (2022) Up-to-date pathologic classification and molecular characteristics of intrahepatic cholangiocarcinoma. Front. Med. 9, 857140. [7] J.-Y. Liau, J.-H. Tsai, R.-H. Yuan, C.-N. Chang, H.-J. Lee, Y.-M. Jeng (2014) Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod. Pathol. 27, 1163-1173. [8] K.S. Ahn, D. O’Brien, Y.N. Kang, T. Mounajjed, Y.H. Kim, T.-S. Kim, J.-P.A. Kocher, L.K. Allotey, M.J. Borad, L.R. Roberts (2019) Prognostic subclass of intrahepatic cholangiocarcinoma by integrative molecular–clinical analysis and potential targeted approach. Hepatol. Int. 13, 490-500. [9] B. Ma, H. Meng, Y. Tian, Y. Wang, T. Song, T. Zhang, Q. Wu, Y. Cui, H. Li, W. Zhang (2020) Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma. BMC cancer 20, 1-12. [10] C.-R. Lin, Y.-K. Lee, C.-J. Chiang, Y.-W. Yang, H.-C. Chang, S.-L. You (2022) Secular trends of intrahepatic cholangiocarcinoma in a high endemic area: A population-based study. World J Gastroenterol 28, 3695. [11] M. Qurashi, M. Vithayathil, S.A. Khan (2023) Epidemiology of cholangiocarcinoma. Eur. J. Surg. Oncol. 107064. [12] S.A. Khan, S. Tavolari, G. Brandi (2019) Cholangiocarcinoma: Epidemiology and risk factors. Liver Int. 39, 19-31. [13] T.M. Welzel, B.I. Graubard, H.B. El–Serag, Y.H. Shaib, A.W. Hsing, J.A. Davila, K.A. McGlynn (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin. Gastroenterol. Hepatol. 5, 1221-1228. [14] 衛生福利部國民健康署. 2024 112年國人死因統計結果. Retrieved from (Accessed 2024, Jul 15). [15] F. Melandro, R.A. Nasto, M. Ginesini, E. Balzano, M.L. Bindi, D. Ghinolfi, Q. Lai (2023) A narrative review of intrahepatic cholangiocarcinoma: a surgical curative option. Chin. Clin. Oncol. 12, 13-13. [16] L. Yin, S. Zhao, H. Zhu, G. Ji, X. Zhang (2021) Primary tumor resection improves survival in patients with multifocal intrahepatic cholangiocarcinoma based on a population study. Sci. Rep. 11, 12166. [17] T. Ioka, M. Kanai, S. Kobayashi, D. Sakai, H. Eguchi, H. Baba, S. Seo, A. Taketomi, T. Takayama, H. Yamaue (2023) Randomized phase III study of gemcitabine, cisplatin plus S‐1 versus gemcitabine, cisplatin for advanced biliary tract cancer (KHBO1401‐MITSUBA). J. Hepato-Biliary-Pancreat. Sci. 30, 102-110. [18] D.-Y. Oh, A. Ruth He, S. Qin, L.-T. Chen, T. Okusaka, A. Vogel, J.W. Kim, T. Suksombooncharoen, M. Ah Lee, M. Kitano (2022) Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evidence 1, EVIDoa2200015. [19] I.S. Choi, K.H. Kim, J.H. Lee, K.J. Suh, J.-W. Kim, J.H. Park, Y.J. Kim, J.-S. Kim, J.H. Kim, J.W. Kim (2021) A randomised phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapy. Eur. J. Cancer 154, 288-295. [20] J. Hyung, I. Kim, K.-p. Kim, B.-Y. Ryoo, J.H. Jeong, M.J. Kang, J. Cheon, B.W. Kang, H. Ryu, J.S. Lee (2023) Treatment with liposomal irinotecan plus fluorouracil and leucovorin for patients with previously treated metastatic biliary tract cancer: the phase 2b NIFTY randomized clinical trial. JAMA Oncol. 9, 692-699. [21] R.C. Martin, K.A. Simo, P. Hansen, F. Rocha, P. Philips, K.M. McMasters, C.M. Tatum, L.R. Kelly, M. Driscoll, V.R. Sharma (2022) Drug-eluting bead, irinotecan therapy of unresectable intrahepatic cholangiocarcinoma (DELTIC) with concomitant systemic gemcitabine and cisplatin. Ann. Surg. Oncol. 29, 5462-5473. [22] A. Cucchetti, A. Cappelli, C. Mosconi, J.H. Zhong, M. Cescon, A.D. Pinna, R. Golfieri (2017) Improving patient selection for selective internal radiation therapy of intra‐hepatic cholangiocarcinoma: a meta‐regression study. Liver Int. 37, 1056-1064. [23] S. Franssen, J.J. Holster, J.S. Jolissaint, L.E. Nooijen, A. Cercek, M.I. D’Angelica, M.Y. Homs, A.C. Wei, V.P. Balachandran, J.A. Drebin (2024) Gemcitabine with cisplatin versus hepatic arterial infusion pump chemotherapy for liver-confined unresectable intrahepatic cholangiocarcinoma. Ann. Surg. Oncol. 31, 115-124. [24] A.X. Zhu, T. Macarulla, M.M. Javle, R.K. Kelley, S.J. Lubner, J. Adeva, J.M. Cleary, D.V. Catenacci, M.J. Borad, J.A. Bridgewater (2021) Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 7, 1669-1677. [25] G.K. Abou-Alfa, V. Sahai, A. Hollebecque, G. Vaccaro, D. Melisi, R. Al-Rajabi, A.S. Paulson, M.J. Borad, D. Gallinson, A.G. Murphy (2020) Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet. Oncol. 21, 671-684. [26] A. Hayashi, K. Misumi, J. Shibahara, J. Arita, Y. Sakamoto, K. Hasegawa, N. Kokudo, M. Fukayama (2016) Distinct clinicopathologic and genetic features of 2 histologic subtypes of intrahepatic cholangiocarcinoma. Am. J. Surg. Pathol. 40, 1021-1030. [27] M. Akita, K. Sofue, K. Fujikura, K. Otani, T. Itoh, T. Ajiki, T. Fukumoto, Y. Zen (2019) Histological and molecular characterization of intrahepatic bile duct cancers suggests an expanded definition of perihilar cholangiocarcinoma. HPB 21, 226-234. [28] M. Akita, K. Fujikura, T. Ajiki, T. Fukumoto, K. Otani, T. Azuma, T. Itoh, Y. Ku, Y. Zen (2017) Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. Mod. Pathol. 30, 986-997. [29] M. Javle, S. Roychowdhury, R.K. Kelley, S. Sadeghi, T. Macarulla, K.H. Weiss, D.-T. Waldschmidt, L. Goyal, I. Borbath, A. El-Khoueiry (2021) Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet. Gastroenterol. Hepatol. 6, 803-815. [30] L. Goyal, F. Meric-Bernstam, A. Hollebecque, J.W. Valle, C. Morizane, T.B. Karasic, T.A. Abrams, J. Furuse, R.K. Kelley, P.A. Cassier (2023) Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N. Engl. J. Med. 388, 228-239. [31] M. Mosele, C. Westphalen, A. Stenzinger, F. Barlesi, A. Bayle, I. Bièche, J. Bonastre, E. Castro, R. Dienstmann, A. Krämer (2024) Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Ann. Oncol. [32] S. Tommasini-Ghelfi, K. Murnan, F.M. Kouri, A.S. Mahajan, J.L. May, A.H. Stegh (2019) Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease. Sci. Adv. 5, eaaw4543. [33] S. Han, Y. Liu, S.J. Cai, M. Qian, J. Ding, M. Larion, M.R. Gilbert, C. Yang (2020) IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. Br. J. Cancer 122, 1580-1589. [34] H. Yang, D. Ye, K.-L. Guan, Y. Xiong (2012) IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin. Cancer Res. 18, 5562-5571. [35] M.J. Wu, L. Shi, J. Merritt, A.X. Zhu, N. Bardeesy (2022) Biology of IDH mutant cholangiocarcinoma. Hepatology 75, 1322-1337. [36] G.L. Robinson, B. Philip, M.R. Guthrie, J.E. Cox, J.P. Robinson, M.W. VanBrocklin, S.L. Holmen (2016) In vitro visualization and characterization of wild type and mutant IDH homo-and heterodimers using bimolecular fluorescence complementation. Cancer Res. Front. 2, 311. [37] L. Dang, D.W. White, S. Gross, B.D. Bennett, M.A. Bittinger, E.M. Driggers, V.R. Fantin, H.G. Jang, S. Jin, M.C. Keenan (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739-744. [38] H. Abla, M. Sollazzo, G. Gasparre, L. Iommarini, A.M. Porcelli, The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?, Semin. Cell Biol., Elsevier, 2020, pp. 26-33. [39] M.-J. Wu, L. Shi, J. Dubrot, J. Merritt, V. Vijay, T.-Y. Wei, E. Kessler, K.E. Olander, R. Adil, A. Pankaj (2022) Mutant IDH inhibits IFNγ–TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. Cancer Discov. 12, 812-835. [40] P.L. Sulkowski, S. Oeck, J. Dow, N.G. Economos, L. Mirfakhraie, Y. Liu, K. Noronha, X. Bao, J. Li, B.M. Shuch (2020) Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 582, 586-591. [41] X. Wang, B.S. Zhao, I.A. Roundtree, Z. Lu, D. Han, H. Ma, X. Weng, K. Chen, H. Shi, C. He (2015) N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388-1399. [42] Y. Gao, X. Ouyang, L. Zuo, Y. Xiao, Y. Sun, C. Chang, X. Qin, S. Yeh (2021) R-2HG downregulates ERα to inhibit cholangiocarcinoma via the FTO/m6A-methylated ERα/miR16-5p/YAP1 signal pathway. Mol. Ther. Oncolytics 23, 65-81. [43] B.I. Fedeles, V. Singh, J.C. Delaney, D. Li, J.M. Essigmann (2015) The AlkB family of Fe (II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J. Biol. Chem. 290, 20734-20742. [44] P. Wang, J. Wu, S. Ma, L. Zhang, J. Yao, K.A. Hoadley, M.D. Wilkerson, C.M. Perou, K.-L. Guan, D. Ye (2015) Oncometabolite D-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep. 13, 2353-2361. [45] Y. Wang, A.T. Wild, S. Turcan, W.H. Wu, C. Sigel, D.S. Klimstra, X. Ma, Y. Gong, E.C. Holland, J.T. Huse (2020) Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas. Sci. Adv. 6, eaaz3221. [46] S.C. Baksh, L.W. Finley (2021) Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases. Trends Cell Biol. 31, 24-36. [47] K. Balamurugan (2016) HIF‐1 at the crossroads of hypoxia, inflammation, and cancer. Int. J. Cancer 138, 1058-1066. [48] G.L. Semenza (2003) Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer. 3, 721-732. [49] P. Koivunen, S. Lee, C.G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J.A. Losman, P. Joensuu, U. Bergmann, S. Gross (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488. [50] J. Shi, B. Sun, W. Shi, H. Zuo, D. Cui, L. Ni, J. Chen (2015) Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour Biol. 36, 655-662. [51] Y. Liu, Y. Lu, O. Celiku, A. Li, Q. Wu, Y. Zhou, C. Yang (2019) Targeting IDH1-mutated malignancies with NRF2 blockade. J. Natl. Cancer Inst. 111, 1033-1041. [52] S.K. McBrayer, J.R. Mayers, G.J. DiNatale, D.D. Shi, J. Khanal, A.A. Chakraborty, K.A. Sarosiek, K.J. Briggs, A.K. Robbins, T. Sewastianik (2018) Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175, 101-116. e25. [53] S.M. Chan, D. Thomas, M.R. Corces-Zimmerman, S. Xavy, S. Rastogi, W.-J. Hong, F. Zhao, B.C. Medeiros, D.A. Tyvoll, R. Majeti (2015) Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21, 178-184. [54] F. Li, X. He, D. Ye, Y. Lin, H. Yu, C. Yao, L. Huang, J. Zhang, F. Wang, S. Xu (2015) NADP+-IDH mutations promote hypersuccinylation that impairs mitochondria respiration and induces apoptosis resistance. Mol. Cell 60, 661-675. [55] C.-j. Han, J.-y. Zheng, L. Sun, H.-c. Yang, Z.-q. Cao, X.-h. Zhang, L.-t. Zheng, X.-c. Zhen (2019) The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-κB pathway. Acta Pharmacol. Sin. 40, 1292-1302. [56] D. Thomas, M. Wu, Y. Nakauchi, M. Zheng, C.A. Thompson-Peach, K. Lim, N. Landberg, T. Köhnke, N. Robinson, S. Kaur (2023) Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability. Cancer Discov. 13, 496-515. [57] X. Wang, Z. Chen, J. Xu, S. Tang, N. An, L. Jiang, Y. Zhang, S. Zhang, Q. Zhang, Y. Shen (2022) SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors. Cell Res. 32, 638-658. [58] K.J. Norsworthy, L. Luo, V. Hsu, R. Gudi, S.E. Dorff, D. Przepiorka, A. Deisseroth, Y.-L. Shen, C.M. Sheth, R. Charlab (2019) FDA approval summary: ivosidenib for relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-1 mutation. Clin. Cancer Res. 25, 3205-3209. [59] S.J. Casak, S. Pradhan, L.A. Fashoyin-Aje, Y. Ren, Y.-L. Shen, Y. Xu, E.C.Y. Chow, Y. Xiong, J.F. Zirklelbach, J. Liu (2022) FDA approval summary: ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an IDH1 mutation. Clin. Cancer Res. 28, 2733-2737. [60] U.S. FDA. 2023 FDA approves ivosidenib for myelodysplastic syndromes. Retrieved from (Accessed 2024, Nov 29). [61] B. Fan, G.K. Abou-Alfa, A.X. Zhu, S.S. Pandya, H. Jia, F. Yin, C. Gliser, Z. Hua, M. Hossain, H. Yang (2024) Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study. Cancer Chemother. Pharmacol. 1-9. [62] R.K. Kelley, J. Bridgewater, G.J. Gores, A.X. Zhu (2020) Systemic therapies for intrahepatic cholangiocarcinoma. J. Hepatol. 72, 353-363. [63] J.M. Cleary, B. Rouaisnel, A. Daina, S. Raghavan, L.A. Roller, B.M. Huffman, H. Singh, P.Y. Wen, N. Bardeesy, V. Zoete (2022) Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma. NPJ Precis. Oncol. 6, 61. [64] R. Reinbold, I.C. Hvinden, P. Rabe, R.A. Herold, A. Finch, J. Wood, M. Morgan, M. Staudt, I.J. Clifton, F.A. Armstrong (2022) Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Nat. Commun. 13, 4785. [65] Z.N. Oltvai, S.E. Harley, D. Koes, S. Michel, E.D. Warlick, A.C. Nelson, S. Yohe, P. Mroz (2021) Assessing acquired resistance to IDH1 inhibitor therapy by full-exon IDH1 sequencing and structural modeling. Mol. Case Stud. 7, a006007. [66] C. Müller, S. Franke, T. Reisländer, V. Keitel, M. Venerito (2024) Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports. Case Rep. Oncol. 17, 753-762. [67] E. Loeuillard, S.R. Fischbach, G.J. Gores, S. Rizvi (2019) Animal models of cholangiocarcinoma. Biochim. Biophys. Acta. 1865, 982-992. [68] G. Notarangelo, J.B. Spinelli, E.M. Perez, G.J. Baker, K. Kurmi, I. Elia, S.A. Stopka, G. Baquer, J.-R. Lin, A.J. Golby (2022) Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function. Science 377, 1519-1529. [69] E. Aguado-Fraile, A. Tassinari, Y. Ishii, C. Sigel, M.A. Lowery, L. Goyal, C. Gliser, L. Jiang, S.S. Pandya, B. Wu (2021) Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma. Future Oncol. 17, 2057-2074. [70] D.F. Calvisi, L. Boulter, J. Vaquero, A. Saborowski, L. Fabris, P.M. Rodrigues, C. Coulouarn, R.E. Castro, O. Segatto, C. Raggi (2023) Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat. Rev. Gastroenterol. Hepatol. 20, 462-480. [71] ClinicalTrials.gov. 2019 Gemcitabine and Cisplatin With Ivosidenib or Pemigatinib for the Treatment of Unresectable or Metastatic Cholangiocarcinoma. Retrieved from https://clinicaltrials.gov/study/NCT04088188. (Accessed 2024, Dec 03). [72] ClinicalTrials.gov. 2024 Venetoclax and Ivosidenib Combined With Chemotherapy in IDH1 Mutated AML (IDH1-AML-2024). Retrieved from https://clinicaltrials.gov/study/NCT06611839. (Accessed 2024, Dec 03). [73] C.A. Lachowiez, S. Loghavi, Z. Zeng, T. Tanaka, Y.J. Kim, H. Uryu, S. Turkalj, N.A. Jakobsen, M.R. Luskin, D.Y. Duose (2023) A phase Ib/II study of ivosidenib with venetoclax±azacitidine in IDH1-mutated myeloid malignancies. Blood Cancer Discov. 4, 276-293. [74] P. Montesinos, C. Recher, S. Vives, E. Zarzycka, J. Wang, G. Bertani, M. Heuser, R.T. Calado, A.C. Schuh, S.-P. Yeh (2022) Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N. Engl. J. Med. 386, 1519-1531. [75] 鄭凱安 (2024) Ivosidenib藥物機制探討與聯合治療藥物篩選應用於IDH1突變型肝內膽管癌治療. 未出版之碩士論文 國立臺灣大學生化科技學系. [76] A. Sule, J. Van Doorn, R.K. Sundaram, S. Ganesa, J.C. Vasquez, R.S. Bindra (2021) Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors. NAR Cancer 3, zcab018. [77] J. Dow, A. Krysztofiak, Y. Liu, D.A. Colon-Rios, F.A. Rogers, P.M. Glazer (2021) Vulnerability of IDH1-mutant cancers to histone deacetylase inhibition via orthogonal suppression of DNA repair. Mol. Cancer Res. 19, 2057-2067. [78] K. Tateishi, H. Wakimoto, A.J. Iafrate, S. Tanaka, F. Loebel, N. Lelic, D. Wiederschain, O. Bedel, G. Deng, B. Zhang (2015) Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28, 773-784. [79] S. Prasopporn, O. Suppramote, B. Ponvilawan, C. Jamyuang, J. Chanthercrob, A. Chaiboonchoe, P. More-Krong, K. Kongsri, M. Suntiparpluacha, R. Chanwat (2022) Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma. Front. Oncol. 12, 1021632. [80] G. Karpel-Massler, C.T. Ishida, E. Bianchetti, Y. Zhang, C. Shu, T. Tsujiuchi, M.A. Banu, F. Garcia, K.A. Roth, J.N. Bruce (2017) Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat. Commun. 8, 1067. [81] O. Suppramote, S. Prasopporn, S. Aroonpruksakul, B. Ponvilawan, J. Makjaroen, M. Suntiparpluacha, K. Korphaisarn, K. Charngkaew, R. Chanwat, T. Pisitkun (2022) The acquired vulnerability caused by CDK4/6 inhibition promotes drug synergism between oxaliplatin and palbociclib in cholangiocarcinoma. Front. Oncol. 12, 877194. [82] X. Song, X. Liu, H. Wang, J. Wang, Y. Qiao, A. Cigliano, K. Utpatel, S. Ribback, M.G. Pilo, M. Serra (2019) Combined CDK4/6 and pan-mTOR inhibition is synergistic against intrahepatic cholangiocarcinoma. Clin. Cancer Res. 25, 403-413. [83] Y.-F. Pan, L. Zhong, M. Wang, T.-Y. Jiang, Y.-k. Lin, Y.-B. Chen, X. Li, H.-P. Hu, H.-B. Zhou, H.-Z. Yan (2024) PTEN status determines therapeutic vulnerability to celastrol in cholangiocarcinoma. Phytomedicine 155790. [84] K. Kaławaj, A. Sławińska-Brych, M. Mizerska-Kowalska, A. Żurek, A. Bojarska-Junak, M. Kandefer-Szerszeń, B. Zdzisińska (2020) Alpha ketoglutarate exerts in vitro anti-osteosarcoma effects through inhibition of cell proliferation, induction of apoptosis via the JNK and caspase 9-dependent mechanism, and suppression of TGF-β and VEGF production and metastatic potential of cells. Int. J. Mol. Sci. 21, 9406. [85] Y. Cai, L. Lv, T. Lu, M. Ding, Z. Yu, X. Chen, X. Zhou, X. Wang (2023) α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis. Cell Death Discov. 9, 182. [86] J.-y. Zhang, B. Zhou, R.-y. Sun, Y.-l. Ai, K. Cheng, F.-n. Li, B.-r. Wang, F.-j. Liu, Z.-h. Jiang, W.-j. Wang (2021) The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res. 31, 980-997. [87] R.M. Chin, X. Fu, M.Y. Pai, L. Vergnes, H. Hwang, G. Deng, S. Diep, B. Lomenick, V.S. Meli, G.C. Monsalve (2014) The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401. [88] P.-S. Liu, H. Wang, X. Li, T. Chao, T. Teav, S. Christen, G. Di Conza, W.-C. Cheng, C.-H. Chou, M. Vavakova (2017) α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985-994. [89] E. Mini, S. Nobili, B. Caciagli, I. Landini, T. Mazzei (2006) Cellular pharmacology of gemcitabine. Ann. Oncol. 17 v7-12. [90] A.H.N. P. (2021) Gemcitabine peptide-based conjugates and their application in targeted tumor therapy. Molecules 26, 364. [91] G. Ciarimboli (2012) Membrane transporters as mediators of cisplatin effects and side effects. Scientifica 2012, 473829. [92] A.B.S. K. (2010) Cellular responses to Cisplatin‐induced DNA damage. J. Nucleic Acids 2010, 201367. [93] S. Dasari, P.B. Tchounwou (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol. 740, 364-78. [94] D.B. Longley, D.P. Harkin, P.G. Johnston (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330-338. [95] Y. Xu, M. Villalona-Calero (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann. Oncol. 13, 1841-1851. [96] L.J. Kuo, L.-X. Yang (2008) γ-H2AX-a novel biomarker for DNA double-strand breaks. In vivo 22, 305-309. [97] X. Fu, R.M. Chin, L. Vergnes, H. Hwang, G. Deng, Y. Xing, M.Y. Pai, S. Li, L. Ta, F. Fazlollahi (2015) 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling. Cell Metab. 22, 508-515. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96946 | - |
| dc.description.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。 | zh_TW |
| dc.description.abstract | 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. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-02-25T16:10:42Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-02-25T16:10:42Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書.... I
謝辭..... II 中文摘要.... III 英文摘要.... IV 目 次.... V 圖 次.... IX 表 次.... X 第 1 章 緒論.... 1 1.1 研究背景.... 1 1.2 研究動機與目的.... 2 1.3 肝內膽管癌 .... 3 1.3.1 肝內膽管癌之概述.... 3 1.3.2 膽管癌之分類.... 4 1.3.3 肝內膽管癌之流行病學.... 6 1.3.4 肝內膽管癌之臨床治療方法.... 7 1.3.5 肝內膽管癌之標靶分子.... 8 1.3.6 肝內膽管癌之標靶治療藥物.... 9 1.4 IDH1 突變型肝內膽管癌 .... 10 1.4.1 突變型 IDH1 蛋白.... 10 1.4.2 D-2-hydroxyglutarate 之作用機制.... 12 1.4.3 突變型 IDH1 臨床標靶藥物——Ivosidenib.... 15 1.4.4 目前臨床治療之困境.... 17 1.4.5 聯合治療.... 18 1.4.6 細胞脆弱性.... 19 1.5 本研究之治療策略.... 25 1.5.1 α-酮戊二酸.... 26 1.5.2 Gemcitabine..... 27 1.5.3 Cisplatin.... 28 1.5.4 5-Fluorouracil..... 29 1.5.5 Irinotecan.... 30 第 2 章 材料與方法.... 31 2.1 實驗材料.... 31 2.1.1 細胞株.... 31 2.1.2 本研究使用之藥物.... 31 2.1.3 細胞培養之實驗材料.... 32 2.1.4 反轉錄聚合酶連鎖反應之實驗材料.... 33 2.1.5 基因序列.... 34 2.1.6 細胞存活率試驗之實驗材料.... 34 2.1.7 D-2-Hydroxyglutarate(D-2HG)檢測之實驗材料.... 35 2.1.8 DNA 損傷檢測之實驗材料.... 35 2.1.9 細胞凋亡分析之實驗材料.... 36 2.1.10 乳酸脫氫酶檢測之實驗材料.... 36 2.1.11 細胞內 ATP 含量檢測之實驗材料.... 36 2.2 實驗儀器.... 37 2.3 細胞培養.... 38 2.3.1 細胞繼代.... 39 2.3.2 冷凍/解凍細胞.... 39 2.3.3 細胞計數與種盤.... 40 2.4 即時定量反轉錄聚合酶連鎖反應.... 41 2.4.1 RNA 萃取.... 41 2.4.2 反轉錄.... 42 2.4.3 即時聚合酶連鎖反應.... 43 2.5 細胞存活率試驗.... 44 2.5.1 實驗步驟.... 44 2.5.2 細胞存活率數據分析.... 45 2.5.3 藥物合併指數數據分析.... 45 2.6 D-2-Hydroxyglutarate(D-2HG)檢測.... 45 2.6.1 樣品製備.... 46 2.6.2 過氯酸去蛋白處理.... 46 2.6.3 D-2HG 檢測.... 47 2.7 DNA 損傷檢測.... 47 2.7.1 實驗步驟.... 48 2.8 細胞凋亡分析.... 49 2.8.1 實驗步驟.... 49 2.9 乳酸脫氫酶檢測.... 50 2.9.1 實驗步驟.... 50 2.10 細胞內 ATP 含量檢測.... 51 2.10.1 實驗步驟.... 51 第 3 章 實驗結果.... 52 3.1 α-KG 促使 mIDH1 肝內膽管癌細胞內 D-2HG 含量上升.... 52 3.2 聯合治療藥物篩選....53 3.3 α-KG 與 5-Fluorouracil 在肝內膽管癌中的協同治療效果.... 56 3.4 α-KG 增加肝內膽管癌細胞對於 5-Fu 的敏感度.... 58 3.5 聯合治療策略未能在 mIDH1 肝內膽管癌中顯著促進 DNA 損傷.... 60 3.6 聯合治療策略協同促進細胞凋亡.... 62 3.7 α-KG 不會誘導細胞焦亡.... 64 3.8 α-KG 促進肝內膽管癌細胞 Thymidylate Synthase 表達下降.... 66 3.9 α-KG 促進肝內膽管癌細胞 ATP 含量受損 .... 68 第 4 章 討論....70 第 5 章 結論與未來展望....74 參考文獻 .... 75 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 異檸檬酸脫氫酶 I 型突變型 | zh_TW |
| dc.subject | α-酮戊二酸 | zh_TW |
| dc.subject | 肝內膽管癌 | zh_TW |
| dc.subject | 聯合治療 | zh_TW |
| dc.subject | 協同效果 | zh_TW |
| dc.subject | Synergism | en |
| dc.subject | α-Ketoglutarate | en |
| dc.subject | Mutant isocitrate dehydrogenase 1 | en |
| dc.subject | Intrahepatic cholangiocarcinoma | en |
| dc.subject | Combination therapy | en |
| dc.title | 探索增強 IDH1 突變型肝內膽管癌的化學治療敏感度之策略 | zh_TW |
| dc.title | Exploring the Strategy to Enhance Chemo-sensitization of IDH1-mutated Intrahepatic Cholangiocarcinoma | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 林宗哲;吳立真;徐士蘭 | zh_TW |
| dc.contributor.oralexamcommittee | Zhong-Zhe Lin;Li-Chen Wu;Shih-Lan Hsu | en |
| dc.subject.keyword | 肝內膽管癌,異檸檬酸脫氫酶 I 型突變型,聯合治療,協同效果,α-酮戊二酸, | zh_TW |
| dc.subject.keyword | Intrahepatic cholangiocarcinoma,Mutant isocitrate dehydrogenase 1,Combination therapy,Synergism,α-Ketoglutarate, | en |
| dc.relation.page | 83 | - |
| dc.identifier.doi | 10.6342/NTU202500348 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-02-05 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 化學系 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 化學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-113-1.pdf 未授權公開取用 | 5.75 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。