肝癌电子杂志 ›› 2024, Vol. 11 ›› Issue (1): 25-29.
裴玺睿1, 李晓航2,*
收稿日期:
2023-02-16
出版日期:
2024-03-31
发布日期:
2024-05-08
通讯作者:
*李晓航,E-mail: med328@163.com
基金资助:
Pei Xirui1, Li Xiaohang2,*
Received:
2023-02-16
Online:
2024-03-31
Published:
2024-05-08
Contact:
*Li Xiaohang, E-mail: med328@163.com
摘要: 肝细胞癌是影响全球健康的重大挑战,已成为我国乃至世界较为常见的肿瘤致死原因。由于肝细胞癌具有隐匿性强、病程进展快、恶性程度高的特点,很多患者在就诊时就已失去手术机会。仑伐替尼具有抑制肿瘤细胞生长、抑制肿瘤血管生成的作用,对不可切除的肝细胞癌患者具有较好疗效,明显延长了患者生存时间,目前已成为治疗不可切除肝细胞癌的一线靶向药物。同时仑伐替尼参与联合治疗肝细胞癌也有积极的治疗效果,在肝细胞癌联合治疗中具有良好的临床应用前景。本文就仑伐替尼治疗肝细胞癌的研究现状进行系统性综述,并对未来该药物的应用前景进行展望。
裴玺睿, 李晓航. 仑伐替尼治疗肝细胞癌的研究进展[J]. 肝癌电子杂志, 2024, 11(1): 25-29.
Pei Xirui, Li Xiaohang. Research progress of lenvatinib for hepatocellular carcinoma[J]. Electronic Journal of Liver Tumor, 2024, 11(1): 25-29.
[1] SUNG H, FERLAY J, SIEGEL R L, et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. [2] LLOVET J M, KELLEY R K, VILLANUEVA A, et al.Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2021, 7(1): 6. [3] FORNER A, REIG M, BRUIX J.Hepatocellular carcinoma[J]. Lancet, 2018, 391(10127): 1301-1314. [4] MEJIA J C, PASKO J.Primary liver cancers: intrahepatic cholangiocarcinoma and hepatocellular carcinoma[J]. Surg Clin North Am, 2020, 100(3): 535-549. [5] CHEN L T, MARTINELLI E, CHENG A L, et al.Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO[J]. Ann Oncol, 2020, 31(3): 334-351. [6] SU G L, ALTAYAR O, O’SHEA R, et al. AGA clinical practice guideline on systemic therapy for hepatocellular carcinoma[J]. Gastroenterology, 2022, 162(3): 920-934. [7] EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER. ELECTRONIC ADDRESS: EASLOFFICE@EASLOFFICE.EU, EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER. EASL clinical practice guidelines: management of hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1): 182-236. [8] LEE Y T, TAN Y J, OON C E.Molecular targeted therapy: treating cancer with specificity[J]. Eur J Pharmacol, 2018, 834: 188-196. [9] LABRIE M, BRUGGE J S, MILLS G B, et al.Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer[J]. Nat Rev Cancer, 2022, 22(6): 323-339. [10] ZHAO Y, ZHANG Y N, WANG K T, et al.Lenvatinib for hepatocellular carcinoma: from preclinical mechanisms to anti-cancer therapy[J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(1): 188391. [11] PATEL S A, NILSSON M B, LE X, et al.Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy[J]. Clin Cancer Res, 2023, 29(1): 30-39. [12] CARMELIET P.VEGF as a key mediator of angiogenesis in cancer[J]. Oncology, 2005, 69(Suppl 3): 4-10. [13] SARKAR C, CHAKROBORTY D, GOSWAMI S, et al. VEGF-A controls the expression of its regulator of angiogenic functions, dopamine D2 receptor, on endothelial cells[J]. J Cell Sci, 2022, 135(11): jcs259617. [14] MA L, HERNANDEZ M O, ZHAO Y, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer[J]. Cancer Cell, 2019, 36(4): 418-430.e6. [15] BALUK P, HASHIZUME H, MCDONALD D M.Cellular abnormalities of blood vessels as targets in cancer[J]. Cur Opin Genet Develop, 2005, 15(1): 102-111. [16] MENG Y M, JIANG X, ZHAO X, et al.Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities[J]. Nat Commun, 2021, 12(1): 6011. [17] AL-SALAMA Z T, SYED Y Y, SCOTT L J. Lenvatinib: a review in hepatocellular carcinoma[J]. Drugs, 2019, 79(6): 665-674. [18] YAMAMOTO Y, MATSUI J, MATSUSHIMA T, et al.Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage[J]. Vasc Cell, 2014, 6: 18. [19] HIRATA E, GIROTTI M R, VIROS A, et al.Intravital imaging reveals how braf inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling[J]. Cancer Cell, 2015, 27(4): 574-588. [20] LIN B C, WANG M, BLACKMORE C, et al.Liver-specific activities of FGF19 require klotho beta[J]. J Biol Chem, 2007, 282(37): 27277-27284. [21] PRIETO-DOMINGUEZ N, SHULL A Y, TENG Y.Making way for suppressing the FGF19/FGFR4 axis in cancer[J]. Future Med Chem, 2018, 10(20): 2457-2469. [22] RAJA A, PARK I, HAQ F, et al.FGF19-FGFR4 signaling in hepatocellular carcinoma[J]. Cells, 2019, 8(6): 536. [23] PHAN P, SAIKIA B B, SONNAILA S, et al.The saga of endocrine FGFs[J]. Cells, 2021, 10(9): 2418. [24] LI X.The FGF metabolic axis[J]. Front Med, 2019, 13(5): 511-530. [25] JOHANSSON H, SØNDERGAARD J N, JORNS C, et al. Chenodeoxycholic acid modulates bile acid synthesis independent of fibroblast growth factor 19 in primary human hepatocytes[J]. Front Endocrinol, 2021, 11: 554922. [26] ZHANG K, CHU K, WU X, et al.Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma[J]. Cancer Research, 2013, 73(4): 1298-1307. [27] OKAMOTO K, IKEMORI-KAWADA M, JESTEL A, et al.Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization[J]. ACS Med Chem Lett, 2015, 6(1): 89-94. [28] MATSUKI M, HOSHI T, YAMAMOTO Y, et al.Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models[J]. Cancer Med, 2018, 7(6): 2641-2653. [29] IKEDA K, KUDO M, KAWAZOE S, et al.Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma[J]. J Gastroenterol, 2017, 52(4): 512-519. [30] CHOI N R, KIM J Y, HONG J H, et al.Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis[J]. BMC Gastroenterol, 2022, 22(1): 135. [31] KUDO M, FINN R S, QIN S, et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173. [32] IWATA H, IMAMURA S, HORI A, et al.Biochemical characterization of TAK-593, a novel VEGFR/PDGFR inhibitor with a two-step slow binding mechanism[J]. Biochemistry, 2011, 50(5): 738-751. [33] TANG W, CHEN Z, ZHANG W, et al.The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects[J]. Signal Transduct Target Ther, 2020, 5(1): 87 . [34] SASAKI R, KANDA T, FUJISAWA M, et al.Different mechanisms of action of regorafenib and lenvatinib on Toll-like receptor-signaling pathways in human hepatoma cell lines[J]. Int J Mol Sci, 2020, 21(9): 3349. [35] ZOU W, WOLCHOK J D, CHEN L. PD-L1 (B7-H1) andPD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers,combinations[J]. Sci Transl Med, 2016, 8(328): 328rv4. [36] WU Q.Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway[J]. Acta Pharmacol Sin, 2021, 42(1): 1-9. [37] CHEN G, HUANG A C, ZHANG W, et al.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response[J]. Nature, 2018, 560(7718): 382-386. [38] KIMURA T, KATO Y, OZAWA Y, et al.Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model[J]. Cancer Sci, 2018, 109(12): 3993-4002. [39] TORRENS L, MONTIRONI C, PUIGVEHÍ M, et al.Immunomodulatory effects of lenvatinib plus anti-programmed cell death protein 1 in mice and rationale for patient enrichment in hepatocellular carcinoma[J]. Hepatology, 2021, 74(5): 2652-2669. [40] YI C, CHEN L, LIN Z, et al.Lenvatinib targets FGF receptor 4 to enhance antitumor immune response of anti-programmed cell death‐1 in HCC[J]. Hepatology, 2021, 74(5): 2544-2560. [41] LI Q, CAO M, YUAN G, et al.Lenvatinib plus camrelizumab vs. lenvatinib monotherapy as first-line treatment for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study[J]. Front Oncol, 2022, 12: 809709. [42] FINN R S, IKEDA M, ZHU A X, et al.Phase Ⅰb study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma[J]. J Clin Oncol, 2020, 38(26): 2960-2970. [43] XU Y, FU S, SHANG K, et al.PD-1 inhibitors plus lenvatinib versus PD-1 inhibitors plus regorafenib in patients with advanced hepatocellular carcinoma after failure of sorafenib[J]. Front Oncol, 2022, 12: 958869. [44] LEE C H, SHAH A Y, RASCO D, et al.Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (study 111/KEYNOTE-146): a phase 1b/2 study[J]. Lancet Oncol, 2021, 22(7): 946-958. [45] MAKKER V, COLOMBO N, CASADO HERRÁEZ A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer[J]. N Engl J Mede, 2022, 386(5): 437-448. [46] ARANCE A, DE LA CRUZ-MERINO L, PETRELLA T M, et al. Phase Ⅱ LEAP-004 study of lenvatinib plus pembrolizumab for melanoma with confirmed progression on a programmed cell death protein-1 or programmed death ligand 1 inhibitor given as monotherapy or in combination[J]. J Clin Oncol, 2023, 41(1): 75-85. [47] RAOUL J L, FORNER A, BOLONDI L, et al.Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence[J]. Cancer Treat Rev, 2019, 72: 28-36. [48] KUDO M.A new treatment option for intermediate-stage hepatocellular carcinoma with high tumor burden: initial lenvatinib therapy with subsequent selective TACE[J]. Liver Cancer, 2019, 8(5): 299-311. [49] CHANG Y, JEONG S W, YOUNG JANG J, et al.Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma[J]. Int J Mol Sci, 2020, 21(21): 8165. [50] HATANAKA T, YATA Y, NAGANUMA A, et al.Treatment strategy for intermediate-stage hepatocellular carcinoma: transarterial chemoembolization, systemic therapy, and conversion therapy[J]. Cancers, 2023, 15(6): 1798. [51] FU Z, LI X, ZHONG J, et al.Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study[J]. Hepatol Int, 2021, 15(3): 663-675. [52] LYU N, WANG X, LI J B, et al.Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phaseⅢ trial (FOHAIC-1)[J]. J Clin Oncol, 2022, 40(5): 468-480. [53] LAI Z, HUANG Y, WEN D, et al.One day versus two days of hepatic arterial infusion with oxaliplatin and fluorouracil for patients with unresectable hepatocellular carcinoma[J]. BMC Med, 2022, 20(1): 415. [54] ZHENG K, ZHU X, FU S, et al.Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib for hepatocellular carcinoma with major portal vein tumor thrombosis: a randomized trial[J]. Radiology, 2022, 303(2): 455-464. [55] JIN H, WANG L, BERNARDS R.Rational combinations of targeted cancer therapies: background, advances and challenges[J]. Nat Rev Drug Discov, 2023, 22(3): 213-234. [56] LONG F, CHEN S, LI R, et al.Efficacy and safety of HAIC alone vs. HAIC combined with lenvatinib for treatment of advanced hepatocellular carcinoma[J]. Med Oncol, 2023, 40(5): 147. [57] IWAMOTO H, SHIMOSE S, SHIRONO T, et al.Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity[J]. Clin Mol Hepatol, 2023, 29(3): 593-604. [58] DENG H, KAN A, LYU N, et al.Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma[J]. Liver Cancer, 2020, 9(3): 338-357. [59] SUN L, XU X, MENG F, et al.Lenvatinib plus transarterial chemoembolization with or without immune checkpoint inhibitors for unresectable hepatocellular carcinoma: a review[J]. Front Oncol, 2022, 12: 980214. [60] CHEN S, WU Z, SHI F, et al.Lenvatinib plus TACE with or without pembrolizumab for the treatment of initially unresectable hepatocellular carcinoma harbouring PD-L1 expression: a retrospective study[J]. J Cancer Res Clin Oncol, 2022, 148(8): 2115-2125. [61] WANG J, XUE Y, LIU R, et al.DEB-TACE with irinotecan versus C-TACE for unresectable intrahepatic cholangiocarcinoma: a prospective clinical study[J]. Front Bioeng Biotechnol, 2023, 10: 1112500. [62] BARGELLINI I, LORENZONI V, LORENZONI G, et al.Duration of response after DEB-TACE compared to lipiodol-TACE in HCC-naïve patients: a propensity score matching analysis[J]. Eur Radiol, 2021, 31(10): 7512-7522. [63] VOGL T J, LAHRSOW M.The role of conventional TACE (cTACE) and DEBIRI-TACE in colorectal cancer liver metastases[J]. Cancers(Basel), 2022, 14(6): 1503. [64] WU S J, RUAN D D, WU Q Y, et al.Safety and efficacy of drug-eluting bead transarterial chemoembolization combined with lenvatinib and Anti-PD-1 antibodies for unresectable hepatocellular carcinoma: a retrospective analysis[J]. J Hepatocell Carcinoma, 2023, 10: 807-820. [65] DHONDT E, LAMBERT B, HERMIE L, et al.90 Y Radioembolization versus drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: results from the TRACE phaseⅡ randomized controlled trial[J]. Radiology, 2022, 303(3): 699-710. [66] LIU J, LI Z, ZHANG W, et al.Comprehensive treatment of trans-arterial chemoembolization plus lenvatinib followed by camrelizumab for advanced hepatocellular carcinoma patients[J]. Front Pharmacol, 2021, 12: 709060. [67] LLOVET J M, VOGEL A, MADOFF D C, et al.Randomized Phase 3 LEAP-012 study: transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment[J]. Cardiovascu Intervent Radiol, 2022, 45(4): 405-412. [68] CAO F, YANG Y, SI T, et al.The efficacy of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a multicenter retrospective study[J]. Front Oncol, 2021, 11: 783480. [69] WENG Y S, CHIANG I T, TSAI J J, et al.Lenvatinib synergistically promotes radiation therapy in hepatocellular carcinoma by inhibiting Src/STAT3/NF-κB-mediated epithelial-mesenchymal transition and metastasis[J]. Int J Radiat Oncol Biol Phys, 2023, 115(3): 719-732. [70] GUPTA R, KADHIM M M, TURKI JALIL A, et al.Multifaceted role of NF-κB in hepatocellular carcinoma therapy: Molecular landscape, therapeutic compounds and nanomaterial approaches[J]. Environ Res, 2023, 228: 115767. [71] UNE N, TAKANO-KASUYA M, KITAMURA N, et al.The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors[J]. Med Oncol, 2021, 38(6): 60. [72] JI X, XU Z, SUN J, et al.Lenvatinib with or without stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective study[J]. Radiat Oncol, 2023, 18(1): 101. [73] LI G, SHU B, ZHENG Z, et al.Safety and efficacy of radiotherapy combined with lenvatinib plus PD-1 inhibitors as neo-adjuvant therapy in hepatocellular carcinoma with portal vein thrombus: protocol of an open-label, single-arm, prospective, multi-center phase I trial[J]. Front Oncol, 2022, 12: 1051916. |
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