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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (6): 685-693    DOI: 10.3724/zdxbyxb-2021-0249
    
Advances in targeted therapy for anaplastic thyroid carcinoma
QIAN Chenhong1,2,JIANG Liehao2,3,XU Shiying2,4,WANG Jiafeng2,3,TAN Zhuo2,3,XIN Ying2,3,GE Minghua1,2,3,*()
1. Graduate School, Bengbu Medical College, Bengbu 233030, Anhui Province, China;
2. Department of Head and Neck Surgery, Center of Otolaryngology, Head and Neck Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China;
3. Zhejiang Provincial Key Laboratory of Endocrine Gland Diseases, Hangzhou 310014, China;
4. The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
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Abstract  

Anaplastic thyroid carcinoma (ATC) is a highly malignant and aggressive thyroid malignancy with rapid onset and poor prognosis. There is no effective treatment for ATC yet. Molecular targeted therapy provides a new idea for ATC treatment. Tyrosine kinase inhibitor lenvatinib has potential in treating ATC patients with favorable efficacy in clinical trials. The effectiveness of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) gene inhibitor dabrafenib in combination with trametinib for the treatment of BRAFV600E positive ATC patients has been demonstrated in clinical trials. The NCCN clinical practice guidelines in oncology has proposed dabrafenib in combination with trametinib as the preferred modality for the treatment of patients with BRAFV600E positive ATC. The immune checkpoint inhibitor pembrolizumab can be applied to treat thyroid cancer with high tumor mutational load and may be considered as the preferred modality for the treatment of ATC patients with high programmed death ligand-1 expression. The mammalian target of rapamycin pathway inhibitors, peroxisome proliferators-activated receptor γ agonists, endothelial growth factor receptors-targeting monoclonal antibody cetuximab and novel vascular blocker fosbretabulin are still in the clinical research stage, which are expected to provide new directions for the development of novel targeted drugs. This article reviews the current research progress on targeted drugs for the treatment of ATC.



Key wordsAnaplastic thyroid carcinoma      Targeted therapy      Immunotherapy      Clinical treatment      Review     
Received: 25 August 2021      Published: 22 March 2022
CLC:  R736.1  
Corresponding Authors: GE Minghua     E-mail: geminghua@hmc.edu.cn
Cite this article:

QIAN Chenhong,JIANG Liehao,XU Shiying,WANG Jiafeng,TAN Zhuo,XIN Ying,GE Minghua. Advances in targeted therapy for anaplastic thyroid carcinoma. J Zhejiang Univ (Med Sci), 2021, 50(6): 685-693.

URL:

https://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0249     OR     https://www.zjujournals.com/med/Y2021/V50/I6/685


甲状腺未分化癌靶向治疗研究进展

甲状腺未分化癌(ATC)是一种恶性程度高、侵袭性强的甲状腺恶性肿瘤,发病迅速,预后差,目前尚缺乏有效治疗手段。分子靶向治疗为ATC治疗提供了一种新思路。酪氨酸激酶抑制剂乐伐替尼在治疗ATC患者临床试验中疗效良好;鼠类肉瘤病毒癌基因同源物B1(BRAF)基因抑制剂达拉非尼联合曲美替尼治疗BRAFV600E阳性ATC患者的有效性已在临床试验中得到证实,2021年美国国家综合癌症网络甲状腺癌临床实践指南中提出达拉非尼联合曲美替尼可作为治疗BRAFV600E阳性ATC患者治疗的首选方式;免疫检查点抑制剂帕博利珠单抗应用于高肿瘤突变负荷甲状腺癌治疗,可作为程序性死亡蛋白1高表达ATC患者的首选方式;哺乳动物雷帕霉素靶蛋白通路抑制剂、过氧化物酶体增殖物激活受体γ激动剂、靶向内皮生长因子受体的单克隆抗体西妥昔单抗及新型血管阻断剂康布瑞汀磷酸二钠仍处于临床研究阶段。本文综述了目前ATC靶向药物治疗的研究进展。


关键词: 甲状腺未分化癌,  靶向治疗,  免疫治疗,  临床治疗,  综述 
[1]   CHINTAKUNTLAWARA V, FOOTER L, KASPERBAUERJ L, et al.Diagnosis and management of anaplastic thyroid cancer[J]Endocrinol Metab Clin N Am, 2019, 48( 1): 269-284.
doi: 10.1016/j.ecl.2018.10.010
[2]   SPARTALISE, ATHANASIADISD I, CHRYSIKOSD, et al.Histone deacetylase inhibitors and anaplastic thyroid carcinoma[J]Anticancer Res, 2019, 39( 3): 1119-1127.
doi: 10.21873/anticanres.13220
[3]   NCCN. NCCN clinical practice guidelines in oncology: thyroid carcinoma[EB/OL]. [2021-04-09]. http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf
[4]   TADESSEF, ASRESG, ABUBEKERA, et al.Spectrum of bcr-abl mutations and treatment outcomes in ethiopian imatinib-resistant patients with chronic myeloid leukemia[J]JCO Glob Oncol, 2021, 1187-1193.
doi: 10.1200/GO.21.00058
[5]   RIUDAVETSM, BOSCH-BARRERAJ, CABEZóN-GUTIéRREZL, et al.Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma[J]Clin Transl Oncol, 2021, 23( 12): 2560-2567.
doi: 10.1007/s12094-021-02661-2
[6]   PERRIF, PEZZULLOL, CHIOFALOM G, et al.Targeted therapy: a new hope for thyroid carcinomas[J]Crit Rev Oncol Hematology, 2015, 94( 1): 55-63.
doi: 10.1016/j.critrevonc.2014.10.012
[7]   ISHIHARAS, ONODAN, NODAS, et al.Sorafenib inhibits vascular endothelial cell proliferation stimulated by anaplastic thyroid cancer cells regardless of BRAF mutation status[J]Int J Oncol, 2019, 55( 5): 1069-1076.
doi: 10.3892/ijo.2019.4881
[8]   SAVVIDESP, NAGAIAHG, LAVERTUP, et al.Phase Ⅱ trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid[J]Thyroid, 2013, 23( 5): 600-604.
doi: 10.1089/thy.2012.0103
[9]   ITOY, ONODAN, ITOK I, et al.Sorafenib in Japanese patients with locally advanced or metastatic medullary thyroid carcinoma and anaplastic thyroid carcinoma[J]Thyroid, 2017, 27( 9): 1142-1148.
doi: 10.1089/thy.2016.0621
[10]   KIMS Y, KIMS M, CHANGH, et al.Synergistic anticancer activity of sorafenib, paclitaxel, and radiation therapy on anaplastic thyroid cancer in vitro and in vivo[J]Head Neck, 2020, 42( 12): 3678-3684.
doi: 10.1002/hed.26431
[11]   YUNH J, KIMH J, KIMJ, et al.Synergistic anticancer activity of N-hydroxy-7-(2-naphthylthio) heptanomide, sorafenib, and radiation therapy in patient-derived anaplastic thyroid cancer models[J]Int J Mol Sci, 2021, 22( 2): 536.
doi: 10.3390/ijms22020536
[12]   HAOZ, WANGP. Lenvatinib in management of solid tumors[J/OL]Oncologist, 2020, 25( 2): e302-e310.
doi: 10.1634/theoncologist.2019-0407
[13]   TAKAHASHIS, KIYOTAN, YAMAZAKIT, et al.A-phase Ⅱ study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer[J]Future Oncol, 2019, 15( 7): 717-726.
doi: 10.2217/fon-2018-0557
[14]   KIMS Y, KIMS M, KIMJ W, et al.Survival with lenvatinib for the treatment of progressive anaplastic thyroid cancer: a single-center, retrospective analysis[J]Front Endocrinol, 2020, 599.
doi: 10.3389/fendo.2020.00599
[15]   BARBAROD, LAPIP, VIACAVAP, et al.Low-intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe[J/OL]BMJ Case Rep, 2020, 13( 12): e236934.
doi: 10.1136/bcr-2020-236934
[16]   RUANX, SHIX, DONGQ, et al.Antitumor effects of anlotinib in thyroid cancer[J]Endocrine-Relat Cancer, 2019, 26( 1): 153-164.
doi: 10.1530/ERC-17-0558
[17]   GUIL, LIUS, ZHANGY, et al.A remarkable and durable response to sintilimab and anlotinib in the first-line treatment of an anaplastic thyroid carcinoma without targetable genomic alterations: a case report[J]Onco Targets Ther, 2021, 2741-2746.
doi: 10.2147/OTT.S305196
[18]   HAH T, LEEJ S, URBAS, et al.A phase Ⅱ study of imatinib in patients with advanced anaplastic thyroid cancer[J]Thyroid, 2010, 20( 9): 975-980.
doi: 10.1089/thy.2010.0057
[19]   PALMBERGE, JOHNSENJ I, PAULSSONJ, et al.Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo[J]Int J Cancer, 2009, 124( 5): 1227-1234.
doi: 10.1002/ijc.24069
[20]   WESTEKEMPERH, FREISTUEHLERM, ANASTASSIOUG, et al.Chemosensitivity of conjunctival melanoma cell lines to single chemotherapeutic agents and combinations[J]Br J Ophthalmol, 2012, 96( 4): 591-596.
doi: 10.1136/bjophthalmol-2011-300686
[21]   KIME S, MATSUSEM, SAENKOV, et al.Imatinib enhances docetaxel-induced apoptosis through inhibition of nuclear factor-κB activation in anaplastic thyroid carcinoma cells[J]Thyroid, 2012, 22( 7): 717-724.
doi: 10.1089/thy.2011.0380
[22]   RAVAUDA, DE LA FOUCHARDIèREC, CARONP, et al.A multicenter phase Ⅱ study of sunitinib in patients with locally advanced or metastatic differentiated, anaplastic or medullary thyroid carcinomas: mature data from the THYSU study[J]Eur J Cancer, 2017, 110-117.
doi: 10.1016/j.ejca.2017.01.029
[23]   BIBLEK C, SUMANV J, MENEFEEM E, et al.A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer[J]J Clin Endocrinol Metab, 2012, 97( 9): 3179-3184.
doi: 10.1210/jc.2012-1520
[24]   ISHAMC R, BOSSOUA R, NEGRONV, et al.Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer[J]Sci Transl Med, 2013, 5( 166): 166ra3.
doi: 10.1126/scitranslmed.3004358
[25]   WANG L, LI W, LIU Y, et al. Clinical study on the safety, efficacy, and prognosis of molecular targeted drug therapy for advanced gastric cancer[J]. Am J Transl Res, 2021,13(5): 4704-4711
[26]   LIH, GENGC, ZHAOH, et al.Multicenter phase Ⅱ study of apatinib single or combination therapy in HER2-negative breast cancer involving chest wall metastasis[J]Chin J Cancer Res, 2021, 33( 2): 243-255.
doi: 10.21147/j.issn.1000-9604.2021.02.11
[27]   ZHAOH, YAOW, MINX, et al.Apatinib plus gefitinib as first-line treatment in advanced egfr-mutant nsclc: the phase Ⅲ active study (ctong1706)[J]J Thoracic Oncol, 2021, 16( 9): 1533-1546.
doi: 10.1016/j.jtho.2021.05.006
[28]   CHENGL, JIAOQ, JINY, et al.Initial therapy of advanced anaplastic thyroid cancer via targeting VEGFR-2: a case report[J]Onco Targets Ther, 2019, 10495-10500.
doi: 10.2147/OTT.S223727
[29]   FENGH, CHENGX, KUANGJ, et al.Apatinib-induced protective autophagy and apoptosis through the AKT-mTOR pathway in anaplastic thyroid cancer[J]Cell Death Dis, 2018, 9( 10): 1030.
doi: 10.1038/s41419-018-1054-3
[30]   GULEM K, CHENY, SANOD, et al.Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model[J]Clin Cancer Res, 2011, 17( 8): 2281-2291.
doi: 10.1158/1078-0432.CCR-10-2762
[31]   FERRARIS M, BOCCIG, DI DESIDEROT, et al.Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo[J]Oncol Rep, 2018, 39( 5): 2306-2314.
doi: 10.3892/or.2018.6305
[32]   BIBLEK C, RYDERM. Evolving molecularly targeted therapies for advanced-stage thyroid cancers[J]Nat Rev Clin Oncol, 2016, 13( 7): 403-416.
doi: 10.1038/nrclinonc.2016.19
[33]   MASHAYEKHI-SARDOOH, HOSSEINJANIH. A new application of mTOR inhibitor drugs as potential therapeutic agents for COVID-19[J]J Basic Clin Physiol Pharmacol, 2021, online,
doi: 10.1515/jbcpp-2020-0495
[34]   CORTADAM, LEVANOS, BODMERD. mTOR signaling in the inner ear as potential target to treat hearing loss[J]Int J Mol Sci, 2021, 22( 12): 6368.
doi: 10.3390/ijms22126368
[35]   SAXTONR A, SABATINID M. mTOR signaling in growth, netabolism, and disease[J]Cell, 2017, 168( 6): 960-976.
doi: 10.1016/j.cell.2017.02.004
[36]   JINN, JIANGT, ROSEND M, et al.Dual inhibition of mitogen-activated protein kinase kinase and mammalian target of rapamycin in differentiated and anaplastic thyroid cancer[J]J Clin Endocrinol Metab, 2009, 94( 10): 4107-4112.
doi: 10.1210/jc.2009-0662
[37]   WAGLEN, GRABINERB C, VAN ALLENE M, et al.Response and acquired resistance to everolimus in anaplastic thyroid cancer[J]N Engl J Med, 2014, 371( 15): 1426-1433.
doi: 10.1056/NEJMoa1403352
[38]   BERNOCCHIO, SIRICOM, CORONAS P, et al.Tumor type agnostic therapy carrying braf mutation: case reports and review of literature[J]Pharmaceuticals, 2021, 14( 2): 159.
doi: 10.3390/ph14020159
[39]   LIAOY, GAOY, CHANGA, et al.Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling[J]J Cell Mol Med, 2020, 24( 20): 12119-12130.
doi: 10.1111/jcmm.15854
[40]   FERRARIS M, ELIAG, RAGUSAF, et al.Novel treatments for anaplastic thyroid carcinoma[J]Gland Surg, 2020, 9( S1): S28-S42.
doi: 10.21037/gs.2019.10.18
[41]   SUBBIAHV, KREITMANR J, WAINBERGZ A, et al.Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer[J]J Clin Oncol, 2018, 36( 1): 7-13.
doi: 10.1200/JCO.2017.73.6785
[42]   WANGJ R, ZAFEREOM E, DADUR, et al.Complete surgical resection following neoadjuvant dabrafenib plus trametinib in BRAFV600E-mutated anaplastic thyroid carcinoma[J]Thyroid, 2019, 29( 8): 1036-1043.
doi: 10.1089/thy.2019.0133
[43]   ROSOVEM H, PEDDIP F, GLASPYJ A. BRAF V600E inhibition in anaplastic thyroid cancer[J]N Engl J Med, 2013, 368( 7): 684-685.
doi: 10.1056/NEJMc1215697
[44]   PILLIT, CANTARAS, MARZOCCHIC, et al.Vemurafenib may overcome TNF-related apoptosis-inducing ligand (TRAIL) resistance in anaplastic thyroid cancer cells[J]Endocrine, 2020, 67( 1): 117-123.
doi: 10.1007/s12020-019-02028-2
[45]   GRECEAM, SORITAUO, DULFD, et al.Potential biomarkers for the efficacy of PD-1-PD-L blockade in cancer[J]Onco Targets Ther, 2021, 5275-5291.
doi: 10.2147/OTT.S283892
[46]   ADAMP, KIRCHERS, SBIERAI, et al.FGF-receptors and PD-L1 in anaplastic and poorly differentiated thyroid cancer: evaluation of the preclinical rationale[J]Front Endocrinol, 2021, 12, 712107.
doi: 10.3389/fendo.2021.712107
[47]   AHNS, KIMT H, KIMS W, et al.Comprehensive screening for PD-L1 expression in thyroid cancer[J]Endocrine-Relat Cancer, 2017, 24( 2): 97-106.
doi: 10.1530/ERC-16-0421
[48]   AGHAJANIM J, COOPERA, MCGUIREH, et al.Pembrolizumab for anaplastic thyroid cancer: a casestudy[J]Cancer Immunol Immunother, 2019, 68( 12): 1921-1934.
doi: 10.1007/s00262-019-02416-7
[49]   DIERKSC, SEUFERTJ, AUMANNK, et al.Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma[J]Thyroid, 2021, 31( 7): 1076-1085.
doi: 10.1089/thy.2020.0322
[50]   KOLLIPARAR, SCHNEIDERB, RADOVICHM, et al.Exceptional response with immunotherapy in a patient with anaplastic thyroid cancer[J]Oncologist, 2017, 22( 10): 1149-1151.
doi: 10.1634/theoncologist.2017-0096
[51]   PRICHARDC N, KIMS, YAZICIY D, et al.Concurrent cetuximab and bevacizumab therapy in a murine orthotopic model of anaplastic thyroid carcinoma[J]Laryngoscope, 2007, 117( 4): 674-679.
doi: 10.1097/MLG.0b013e318031055e
[52]   KIMS, PRICHARDC N, YOUNESM N, et al.Cetuximab and irinotecan interact synergistically to inhibit the growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice[J]Clin Cancer Res, 2006, 12( 2): 600-607.
doi: 10.1158/1078-0432.CCR-05-1325
[53]   SMALLRIDGER C, COPLANDJ A, BROSEM S, et al.Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial[J]J Clin Endocrinol Metab, 2013, 98( 6): 2392-2400.
doi: 10.1210/jc.2013-1106
[54]   DZIBAJ M, MARCINEKR, VENKATARAMANG, et al.Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors[J]Thyroid, 2002, 12( 12): 1063-1070.
doi: 10.1089/105072502321085153
[55]   MOONEYC J, NAGAIAHG, FUP, et al.A phase Ⅱ trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome[J]Thyroid, 2009, 19( 3): 233-240.
doi: 10.1089/thy.2008.0321
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