胆管癌的靶向治疗研究进展
Research Progress in Targeted Therapy for Cholangiocarcinoma
DOI: 10.12677/acm.2024.1482383, PDF,   
作者: 牛 蒙：延安大学医学院，陕西 延安；李晓勇：延安大学附属医院肝胆外科，陕西 延安
关键词: 胆管癌；靶向治疗；治疗；Cholangiocarcinoma； Targeted Therapy； Treatment
摘要: 胆管癌(CCA)是一种起源于胆管及其分支上皮的恶性肿瘤。由于其异质性高，早期没有特异性的临床指征，诊断常为晚期CCA。手术切除术后5年生存率(长期生存率)很差。吉西他滨联合铂类治疗方案已被用作晚期患者的一线化疗。近年来，针对多种恶性肿瘤的靶向治疗取得了长足进展，在晚期CCA中显示出良好的疗效和安全性。然而，目前CCA的靶向治疗仍存在不良反应、耐药性、个体差异等诸多挑战。因此，研究需要进一步深入探索CCA恶性肿瘤的靶向治疗机制，开发更有效、更安全的药物，并根据患者特点精准制定方案，以进一步改善患者未来的预后。本文综述了CCA靶向治疗的最新进展，旨在为CCA靶向治疗的研究和临床工作提供策略。
Abstract: Cholangiocarcinoma (CCA) is a malignant tumor that originates from the epithelial epithelium of the bile ducts and their branches. Due to its high heterogeneity, there is no specific clinical indication for the early stage, and the diagnosis is often advanced CCA. The 5-year survival rate (long-term survival) after surgical resection is poor. Gemcitabine plus platinum-based regimens have been used as first-line chemotherapy for patients with advanced disease. In recent years, significant progress has been made in targeted therapy for a variety of malignancies, showing good efficacy and safety in advanced CCA. However, there are still many challenges in the targeted therapy of CCA, such as adverse reactions, drug resistance, and individual differences. Therefore, it is necessary to further explore the targeted therapy mechanism of CCA malignancies, develop more effective and safer drugs, and formulate precise plans according to the characteristics of patients to further improve the prognosis of patients in the future. This article reviews the latest advances in CCA-targeted therapy, aiming to provide strategies for the research and clinical work of CCA-targeted therapy.
文章引用：牛蒙, 李晓勇. 胆管癌的靶向治疗研究进展[J]. 临床医学进展, 2024, 14(8): 1499-1506. https://doi.org/10.12677/acm.2024.1482383

参考文献

[1] Brindley, P.J., Bachini, M., Ilyas, S.I., Khan, S.A., Loukas, A., Sirica, A.E., et al. (2021) Cholangiocarcinoma. Nature Reviews Disease Primers, 7, Article No. 65. [Google Scholar] [CrossRef] [PubMed]
[2] Cardinale, V. (2019) Classifications and Misclassification in Cholangiocarcinoma. Liver International, 39, 260-262. [Google Scholar] [CrossRef] [PubMed]
[3] Elvevi, A., Laffusa, A., Scaravaglio, M., Rossi, R.E., Longarini, R., Stagno, A.M., et al. (2022) Clinical Treatment of Cholangiocarcinoma: An Updated Comprehensive Review. Annals of Hepatology, 27, Article 100737. [Google Scholar] [CrossRef] [PubMed]
[4] Chen, C., Jiang, J., Fang, M., Zhou, L., Chen, Y., Zhou, J., et al. (2020) MicroRNA-129-2-3p Directly Targets Wip1 to Suppress the Proliferation and Invasion of Intrahepatic Cholangiocarcinoma. Journal of Cancer, 11, 3216-3224. [Google Scholar] [CrossRef] [PubMed]
[5] Liu, S., Liu, X., Li, X., Li, O., Yi, W., Khan, J., et al. (2020) Application of Laparoscopic Radical Resection for Type III and IV Hilar Cholangiocarcinoma Treatment. Gastroenterology Research and Practice, 2020, Article 1506275. [Google Scholar] [CrossRef] [PubMed]
[6] Montal, R., Sia, D., Montironi, C., Leow, W.Q., Esteban-Fabró, R., Pinyol, R., et al. (2020) Molecular Classification and Therapeutic Targets in Extrahepatic Cholangiocarcinoma. Journal of Hepatology, 73, 315-327. [Google Scholar] [CrossRef] [PubMed]
[7] Wahida, A., Buschhorn, L., Fröhling, S., Jost, P.J., Schneeweiss, A., Lichter, P., et al. (2022) The Coming Decade in Precision Oncology: Six Riddles. Nature Reviews Cancer, 23, 43-54. [Google Scholar] [CrossRef] [PubMed]
[8] Capuozzo, M., Santorsola, M., Landi, L., Granata, V., Perri, F., Celotto, V., et al. (2022) Evolution of Treatment in Advanced Cholangiocarcinoma: Old and New Towards Precision Oncology. International Journal of Molecular Sciences, 23, Article 15124. [Google Scholar] [CrossRef] [PubMed]
[9] Jiang, Y., Liu, Y., Xiao, Y., Hu, X., Jiang, L., Zuo, W., et al. (2020) Molecular Subtyping and Genomic Profiling Expand Precision Medicine in Refractory Metastatic Triple-Negative Breast Cancer: The FUTURE Trial. Cell Research, 31, 178-186. [Google Scholar] [CrossRef] [PubMed]
[10] Yu, Y., Chen, K. and Fan, Y. (2022) Extensive‐Stage Small‐Cell Lung Cancer: Current Management and Future Directions. International Journal of Cancer, 152, 2243-2256. [Google Scholar] [CrossRef] [PubMed]
[11] Llovet, J.M., Montal, R., Sia, D. and Finn, R.S. (2018) Molecular Therapies and Precision Medicine for Hepatocellular Carcinoma. Nature Reviews Clinical Oncology, 15, 599-616. [Google Scholar] [CrossRef] [PubMed]
[12] Ross, J.S., Wang, K., Gay, L., Al-Rohil, R., Rand, J.V., Jones, D.M., et al. (2014) New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing. The Oncologist, 19, 235-242. [Google Scholar] [CrossRef] [PubMed]
[13] Javle, M., Bekaii‐Saab, T., Jain, A., Wang, Y., Kelley, R.K., Wang, K., et al. (2016) Biliary Cancer: Utility of Next‐Generation Sequencing for Clinical Management. Cancer, 122, 3838-3847. [Google Scholar] [CrossRef] [PubMed]
[14] Massironi, S., Pilla, L., Elvevi, A., Longarini, R., Rossi, R.E., Bidoli, P., et al. (2020) New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma. Cells, 9, Article 688. [Google Scholar] [CrossRef] [PubMed]
[15] Wagner, J.P., Wolf-Yadlin, A., Sevecka, M., Grenier, J.K., Root, D.E., Lauffenburger, D.A., et al. (2013) Receptor Tyrosine Kinases Fall into Distinct Classes Based on Their Inferred Signaling Networks. Science Signaling, 6, ra58. [Google Scholar] [CrossRef] [PubMed]
[16] Katoh, M. (2018) Fibroblast Growth Factor Receptors as Treatment Targets in Clinical Oncology. Nature Reviews Clinical Oncology, 16, 105-122. [Google Scholar] [CrossRef] [PubMed]
[17] Ornitz, D.M. and Itoh, N. (2015) The Fibroblast Growth Factor Signaling Pathway. WIREs Developmental Biology, 4, 215-266. [Google Scholar] [CrossRef] [PubMed]
[18] Javle, M., Lowery, M., Shroff, R.T., Weiss, K.H., Springfeld, C., Borad, M.J., et al. (2018) Phase II Study of BGJ398 in Patients with FGFR-Altered Advanced Cholangiocarcinoma. Journal of Clinical Oncology, 36, 276-282. [Google Scholar] [CrossRef] [PubMed]
[19] Salati, M., Caputo, F., Baldessari, C., Carotenuto, P., Messina, M., Caramaschi, S., et al. (2021) The Evolving Role of FGFR2 Inhibitors in Intrahepatic Cholangiocarcinoma: From Molecular Biology to Clinical Targeting. Cancer Management and Research, 13, 7747-7757. [Google Scholar] [CrossRef] [PubMed]
[20] Yang, R., Song, Y., Shakoor, K., Yi, W., Peng, C. and Liu, S. (2022) Insights into the Role of STAT3 in Intrahepatic Cholangiocarcinoma (Review). Molecular Medicine Reports, 25, Article No. 171. [Google Scholar] [CrossRef] [PubMed]
[21] Javle, M.M., Shaib, W.L., Braun, S., Engelhardt, M., Borad, M.J., Abou-Alfa, G.K., et al. (2020) FIDES-01, a Phase II Study of Derazantinib in Patients with Unresectable Intrahepatic Cholangiocarcinoma (iCCA) and FGFR2 Fusions and Mutations or Amplifications (M/A). Journal of Clinical Oncology, 38, TPS597. [Google Scholar] [CrossRef] 
[22] Huang, E.J. and Reichardt, L.F. (2001) Neurotrophins: Roles in Neuronal Development and Function. Annual Review of Neuroscience, 24, 677-736. [Google Scholar] [CrossRef] [PubMed]
[23] Kheder, E.S. and Hong, D.S. (2018) Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins. Clinical Cancer Research, 24, 5807-5814. [Google Scholar] [CrossRef] [PubMed]
[24] Drilon, A., Laetsch, T.W., Kummar, S., DuBois, S.G., Lassen, U.N., Demetri, G.D., et al. (2018) Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. New England Journal of Medicine, 378, 731-739. [Google Scholar] [CrossRef] [PubMed]
[25] Luvira, V., Satitkarnmanee, E., Pugkhem, A., Kietpeerakool, C., Lumbiganon, P. and Pattanittum, P. (2021) Postoperative Adjuvant Chemotherapy for Resectable Cholangiocarcinoma. Cochrane Database of Systematic Reviews, No. 9, CD012814. [Google Scholar] [CrossRef] [PubMed]
[26] Drilon, A. (2019) TRK Inhibitors in TRK Fusion-Positive Cancers. Annals of Oncology, 30, viii23-viii30. [Google Scholar] [CrossRef] [PubMed]
[27] Drilon, A., Siena, S., Ou, S.I., Patel, M., Ahn, M.J., Lee, J., et al. (2017) Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and Startrk-1). Cancer Discovery, 7, 400-409. [Google Scholar] [CrossRef] [PubMed]
[28] Drilon, A., Nagasubramanian, R., Blake, J.F., Ku, N., Tuch, B.B., Ebata, K., et al. (2017) A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discovery, 7, 963-972. [Google Scholar] [CrossRef] [PubMed]
[29] Lee, J., Park, S.H., Chang, H., Kim, J.S., Choi, H.J., Lee, M.A., et al. (2012) Gemcitabine and Oxaliplatin with or without Erlotinib in Advanced Biliary-Tract Cancer: A Multicentre, Open-Label, Randomised, Phase 3 Study. The Lancet Oncology, 13, 181-188. [Google Scholar] [CrossRef] [PubMed]
[30] Malka, D., Cervera, P., Foulon, S., Trarbach, T., de la Fouchardière, C., Boucher, E., et al. (2014) Gemcitabine and Oxaliplatin with or without Cetuximab in Advanced Biliary-Tract Cancer (BINGO): A Randomised, Open-Label, Non-Comparative Phase 2 Trial. The Lancet Oncology, 15, 819-828. [Google Scholar] [CrossRef] [PubMed]
[31] Gruenberger, B., Schueller, J., Heubrandtner, U., Wrba, F., Tamandl, D., Kaczirek, K., et al. (2010) Cetuximab, Gemcitabine, and Oxaliplatin in Patients with Unresectable Advanced or Metastatic Biliary Tract Cancer: A Phase 2 Study. The Lancet Oncology, 11, 1142-1148. [Google Scholar] [CrossRef] [PubMed]
[32] Sohal, D.P.S., Mykulowycz, K., Uehara, T., Teitelbaum, U.R., Damjanov, N., Giantonio, B.J., et al. (2013) A Phase II Trial of Gemcitabine, Irinotecan and Panitumumab in Advanced Cholangiocarcinoma. Annals of Oncology, 24, 3061-3065. [Google Scholar] [CrossRef] [PubMed]
[33] Tsukada, Y., Fang, J., Erdjument-Bromage, H., Warren, M.E., Borchers, C.H., Tempst, P., et al. (2005) Histone Demethylation by a Family of Jmjc Domain-Containing Proteins. Nature, 439, 811-816. [Google Scholar] [CrossRef] [PubMed]
[34] Dang, L. and Su, S.M. (2017) Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development. Annual Review of Biochemistry, 86, 305-331. [Google Scholar] [CrossRef] [PubMed]
[35] Yang, H., Ye, D., Guan, K. and Xiong, Y. (2012) IDH1 and IDH2 Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives. Clinical Cancer Research, 18, 5562-5571. [Google Scholar] [CrossRef] [PubMed]
[36] Lee, H. and Ross, J.S. (2017) The Potential Role of Comprehensive Genomic Profiling to Guide Targeted Therapy for Patients with Biliary Cancer. Therapeutic Advances in Gastroenterology, 10, 507-520. [Google Scholar] [CrossRef] [PubMed]
[37] Ilyas, S.I. and Gores, G.J. (2017) Emerging Molecular Therapeutic Targets for Cholangiocarcinoma. Journal of Hepatology, 67, 632-644. [Google Scholar] [CrossRef] [PubMed]
[38] Abou-Alfa, G.K., Macarulla, T., Javle, M.M., Kelley, R.K., Lubner, S.J., Adeva, J., et al. (2020) Ivosidenib in IDH1-Mutant, Chemotherapy-Refractory Cholangiocarcinoma (ClariDHy): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study. The Lancet Oncology, 21, 796-807. [Google Scholar] [CrossRef] [PubMed]
[39] Golub, D., Iyengar, N., Dogra, S., Wong, T., Bready, D., Tang, K., et al. (2019) Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Frontiers in Oncology, 9, Article 417. [Google Scholar] [CrossRef] [PubMed]
[40] Valle, J.W., Lamarca, A., Goyal, L., Barriuso, J. and Zhu, A.X. (2017) New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discovery, 7, 943-962. [Google Scholar] [CrossRef] [PubMed]
[41] Hyman, D.M., Puzanov, I., Subbiah, V., Faris, J.E., Chau, I., Blay, J., et al. (2015) Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. New England Journal of Medicine, 373, 726-736. [Google Scholar] [CrossRef] [PubMed]
[42] Planchard, D., Smit, E.F., Groen, H.J.M., Mazieres, J., Besse, B., Helland, Å., et al. (2017) Dabrafenib Plus Trametinib in Patients with Previously Untreated BRAFV600E-Mutant Metastatic Non-Small-Cell Lung Cancer: An Open-Label, Phase 2 Trial. The Lancet Oncology, 18, 1307-1316. [Google Scholar] [CrossRef] [PubMed]
[43] Taylor, M.H., Schmidt, E.V., Dutcus, C., Pinheiro, E.M., Funahashi, Y., Lubiniecki, G., et al. (2020) The LEAP Program: Lenvatinib Plus Pembrolizumab for the Treatment of Advanced Solid Tumors. Future Oncology, 17, 637-648. [Google Scholar] [CrossRef] [PubMed]
[44] Lin, J., Yang, X., Long, J., Zhao, S., Mao, J., Wang, D., et al. (2020) Pembrolizumab Combined with Lenvatinib as Non-First-Line Therapy in Patients with Refractory Biliary Tract Carcinoma. Hepatobiliary Surgery and Nutrition, 9, 414-424. [Google Scholar] [CrossRef] [PubMed]
[45] Yarchoan, M., Cope, L., Ruggieri, A.N., Anders, R.A., Noonan, A.M., Goff, L.W., et al. (2021) Multicenter Randomized Phase II Trial of Atezolizumab with or without Cobimetinib in Biliary Tract Cancers. Journal of Clinical Investigation, 131, e152670. [Google Scholar] [CrossRef] [PubMed]

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