放射性碘难治性甲状腺癌的临床试验现状及未来展望

李汝平; 杨辉

doi:10.19401/j.cnki.1007-3639.2025.01.005

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放射性碘难治性甲状腺癌的临床试验现状及未来展望

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- 放射性碘难治性甲状腺癌的临床试验现状及未来展望
- Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer
- 中国癌症杂志 2025年35卷第1期页码：40-48
- 作者机构：
  
  1. 郑州大学附属肿瘤医院（河南省肿瘤医院）核医学科，河南郑州 450008
  2. 河南省肿瘤核医学精准诊疗医学重点实验室，河南郑州 450003
- 作者简介：
  
  [ "李汝平（ORCID: 0009-0002-7927-6036），博士，主治医师。" ]
  [ "杨辉，主任医师，硕士研究生导师，郑州大学附属肿瘤医院核医学科主任，河南省肿瘤核医学精准诊疗医学重点实验室主任，河南省甲状腺疾病诊疗中心副主任、河南省甲状腺癌MDT学组副组长。擅长甲状腺癌131I治疗及综合治疗、肿瘤125I粒子植入治疗、89Sr治疗骨转移瘤、223Ra治疗前列腺癌骨转移、90Y微球治疗肝肿瘤、177Lu-PSMA治疗前列腺癌等核素治疗及相关研究，核医学影像诊断。发表论文50余篇，参编专著4部，获科技成果奖5项和国家专利2项。主要兼职：中国抗癌协会肿瘤核医学专业委员会主任委员，河南省医师协会核医学医师分会会长，中国临床肿瘤学会核医学专家委员会副主任委员，中国医师协会核医学医师分会常委，中国医学影像技术研究会核医学分会常委。《国际放射医学核医学杂志》《肿瘤影像学》常务编委，《中华核医学与分子影像杂志》特约审稿专家。" ]
- 基金信息：
  
  河南省科技攻关项目(242102311045);国家自然科学基金(82402330);河南省卫生健康委员会科技攻关项目(LHGJ20240132)
- DOI：10.19401/j.cnki.1007-3639.2025.01.005
  中图分类号： R736.1
- 收稿：2024-12-13，
  
  修回：2025-01-21，
  
  纸质出版：2025-01-30
- 稿件说明：
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李汝平, 杨辉. 放射性碘难治性甲状腺癌的临床试验现状及未来展望[J]. 中国癌症杂志, 2025,35(1):40-48.

Ruping LI, Hui YANG. Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer[J]. China Oncology, 2025, 35(1): 40-48.
李汝平, 杨辉. 放射性碘难治性甲状腺癌的临床试验现状及未来展望[J]. 中国癌症杂志, 2025,35(1):40-48. DOI： 10.19401/j.cnki.1007-3639.2025.01.005.

Ruping LI, Hui YANG. Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer[J]. China Oncology, 2025, 35(1): 40-48. DOI： 10.19401/j.cnki.1007-3639.2025.01.005.

摘要

放射性碘难治性甲状腺癌（radioiodine-refractory thyroid cancer，RAIR-TC）是指无法或很难从

131

I治疗中获益的甲状腺癌，目前常涉及的RAIR-TC主要是原本分化较好的分化型甲状腺癌（differentiated thyroid cancer，DTC），随着病程或

131

I治疗后逐渐出现不摄取

131

I现象。与能够摄取

131

I的DTC相比，RAIR-TC的恶性程度明显增加，疾病进展较快，死亡风险较高。因此，RAIR-TC的后续治疗已成为国际甲状腺癌研究领域的热点和难点。RAIR-TC的治疗发展经历了多个阶段，从最初的放射性碘治疗到近年来靶向药物的引入，再到免疫治疗的尝试，治疗手段逐步多样化。分子靶向治疗，特别是酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKI），为RAIR-TC患者提供了新的治疗选择，但单一靶向治疗的耐药性迅速显现，成为治疗的瓶颈。磷脂酰肌醇3-激酶（phosphoinositide3-kinase，PI3K）/蛋白激酶B（protein kinase，AKT）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）通路和表皮生长因子受体（epidermal growth factor receptor，EGFR）通路的激活是肿瘤逃逸靶向治疗的主要途径。因此，联合治疗策略应运而生，通过靶向多个信号转导通路、优化联合药物的使用，尝试克服单药耐药性。此外，结合患者的分子生物学特征（如

BRAF

突变、肿瘤免疫表型等）设计个性化治疗方案，已成为研究的热点。免疫治疗，特别是免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）[如派姆单抗（pembrolizumab）

]

，在程序性死亡蛋白配体-1（programmed death ligand-1，PD-L1）高表达的RAIR-TC患者中取得了一定的临床效果。然而，由于RAIR-TC的免疫原性较低，免疫治疗的总体缓解率仍较低，通常为10%~15%。近年来，靶向治疗与免疫治疗的联合治疗策略，如BRAF抑制剂、血管内皮生长因子受体（vascular endothelial growth factor receptor，VEGFR）抑制剂联合程序性死亡蛋白-1（programmed death-1，PD-1）抑制剂的三联疗法，在部分患者中显示出显著疗效，甚至出现完全缓解，为提高免疫治疗效果开辟了新的方向，但如何优化联合治疗方案、克服耐药性和不良反应仍是未来研究的难点。此外，表观遗传学和代谢组学的研究为RAIR-TC的治疗提供了新的思路。DNA甲基化、组蛋白去乙酰化等表观遗传机制在RAIR-TC的进展和耐药中起着重要作用，其相关抑制剂可能恢复肿瘤对放射性碘的摄取能力，从而增强

131

I治疗的敏感性。尽管表观遗传学的研究取得了初步进展，但临床试验仍处于早期阶段，需进一步验证其应用潜力。肿瘤代谢异常，尤其是乳酸代谢和谷氨酰胺代谢的改变，在肿瘤生长和耐药中发挥重要作用。谷氨酰胺合成酶（glutamine synthetase，GLS）抑制剂和乳酸脱氢酶A（lactate dehydrogenase A，LDHA）抑制剂能有效地抑制肿瘤生长，并可能逆转耐药性。因此，开发针对这些代谢靶点的创新药物，成为未来治疗RAIR-TC的重要方

向。尽管现有疗法在一定程度上改善了RAIR-TC患者的生存期，仍面临耐药性、不良反应及肿瘤异质性等挑战。未来的研究应聚焦于优化联合治疗方案、开发新靶点药物及提高免疫治疗的适应性。在多学科协作和技术创新的推动下，RAIR-TC的治疗有望在未来取得突破，进而改善患者的预后和生活质量。

Abstract

Radioiodine-refractory thyroid cancer (RAIR-TC) refers to thyroid cancer that is unable to or difficult to benefit from

131

I treatment. The type of RAIR-TC we commonly encounter is differentiated thyroid cancer (DTC)

which is originally well-differentiated but gradually loses its ability to take up iodine during disease progression or after

131

I treatment. Compared to DTC that can still take up

131

RAIR-TC is more malignant

progresses more rapidly

and carries a higher risk of death. Therefore

the subsequent treatment of RAIR-TC has become a hotspot and a challenge in the field of international thyroid cancer research. The treatment of RAIR-TC has evolved through several stages

from initial radioactive iodine therapy to the introduction of targeted drugs in recent years

followed by attempts at immunotherapy

diversifying treatment options. Molecular targeted therapy

especially tyrosine kinase inhibitors (TKIs)

has provided new treatment choices for RAIR-TC patients. However

resistance to single-agent targeted therapy has quickly emerged as a bottleneck in treatment efficacy. Studies have shown that the activation of the phosphoinositide3-kinase (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and epidermal growth factor receptor (EGFR) pathway is the main mechanism by which tumors evade targeted therapy. As a result

combination therapy strategies have emerged

aiming to target multiple signaling pathways and optimize the use of combined drugs to overcome single-drug resistance. Additionally

designing personalized treatment plans based on patients’ molecular features (such as

BRAF

mutations and tumor immune phenotypes) has become a research focus. Immunotherapy

especially immune checkpoint inhibitors (IC

Is) such as pembrolizumab

has shown some clinical effect in RAIR-TC patients with high level of programmed death ligand-1 (PD-L1) expression. However

due to the low immunogenicity of RAIR-TC

the overall response rate to immunotherapy remains relatively low

typically ranging from 10% to 15%. In recent years

combination strategies involving targeted therapy and immunotherapy

such as the triplet therapy of BRAF inhibitors

vascular endothelial growth factor receptor (VEGFR) inhibitors

and programmed death-1 (PD-1) inhibitors

have shown significant efficacy in some patients

even achieving complete remission. This offers new directions for improving the efficacy of immunotherapy

however optimizing combination therapy

overcoming resistance

and managing side effects remain key challenges for future research. Moreover

epigenetics and metabolism studies have provided new insights into the treatment of RAIR-TC. Research has shown that epigenetic mechanisms

such as DNA methylation and histone deacetylation

play important roles in the progression and resistance of RAIR-TC. Inhibitors targeting these mechanisms may restore the ability of tumor to take up radioactive iodine

thus enhancing sensitivity to

131

I therapy. Although progress has been made in epigenetic research

clinical trials are still in the early stages

and further verification of their potential is needed. Tumor metabolic abnormalities

particularly changes in lactate and glutamine metabolism

play crucial roles in tumor growth and resistance. Studies have found that glutamine synthetase (GLS) inhibitors and lactate dehydrogenase A (LDHA) inhibitors can effectively suppress tumor growth and potentially reverse resistance. Thus

the development of innovative drugs targeting these metabolic pathways is becoming an important direction for future RAIR-TC treatments. Although current therapies have improved the survival of RAIR-TC patients to some extent

challenges such as resistance

toxic reactions and tumor heterogeneity remain. Future

research should focus on optimizing combination treatment strategies

developing new targeted drugs

and improving the adaptability of immunotherapy in clinical trials. With the advancement of multidisciplinary collaboration and technological innovation

breakthroughs in RAIR-TC treatment are expected in the future

ultimately improving patient prognosis and quality of life.

关键词

Keywords

references

HAMIDI S , HOFMANN M C , IYER P C , et al. Review article: new treatments for advanced differentiated thyroid cancers and potential mechanisms of drug resistance [J ] . Front Endocrinol (Lausanne) , 2023 , 14 : 1176731 .

JI X Y , LIANG W L , LV G X , et al. Efficacy and safety of targeted therapeutics for patients with radioiodine-refractory differentiated thyroid cancer: systematic review and network meta-analysis [J ] . Front Pharmacol , 2022 , 13 : 933648 .

BUFFET C , WASSERMANN J , HECHT F , et al. Redifferentiation of radioiodine-refractory thyroid cancers [J ] . Endocr Relat Cancer , 27 ( 5 ): R113-R132.

SONG M Y , LIU Q , SUN W , et al. Crosstalk between thyroid carcinoma and tumor-correlated immune cells in the tumor microenvironment [J ] . Cancers (Basel) , 2023 , 15 ( 10 ): 2863.

EZZAT S , PASTERNAK J D , RAJARAMAN M , et al. Multidisciplinary Canadian consensus on the multimodal management of high-risk and radioactive iodine-refractory thyroid carcinoma [J ] . Front Oncol , 2024 , 14 : 1437360 .

WEITZMAN S P , SHERMAN S I . Novel drug treatments of progressive radioiodine-refractory differentiated thyroid cancer [J ] . Endocrinol Metab Clin North Am , 2019 , 48 ( 1 ): 253 - 268 .

VACCHER E , SCHIOPPA O , MARTELLOTTA F , et al. Safety profiles and pharmacovigilance considerations for recently patented anticancer drugs: advanced thyroid cancer [J ] . Recent Pat Anticancer Drug Discov , 2019 , 14 ( 3 ): 226 - 241 . DOI: 10.2174/1574892814666190726143011 http://doi.org/10.2174/1574892814666190726143011

SCHLUMBERGER M , TAHARA M , WIRTH L J , et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer [J ] . N Engl J Med , 2015 , 372 ( 7 ): 621 - 630 .

DICKERSON K , MILAS M , METZGER R , et al. Neoadjuvant systemic therapy for inoperable differentiated thyroid cancers: Impact on tumor resectability [J ] . Surgery , 2025 , 177 : 108836 .

KIYOTA N , TAHARA M , ROBINSON B , et al. Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial [J ] . Cancer , 2022 , 128 ( 12 ): 2281 - 2287 . DOI: 10.1002/cncr.34181 http://doi.org/10.1002/cncr.34181

LIN Y , QIN S , LI Z , et al. Apatinib vs placebo in patients with locally advanced or metastatic , radioactive iodine-refractory differentiated thyroid cancer: the REALITY randomized clinical trial [J ] . JAMA Oncol , 2022 , 8 ( 2 ): 242 - 250 .

LI D P , CHI Y , CHEN X H , et al. Anlotinib in locally advanced or metastatic medullary thyroid carcinoma: a randomized, double-blind phase ⅡB trial [J ] . Clin Cancer Res , 2021 , 27 ( 13 ): 3567 - 3575 .

LIN Y S , QIN S K , YANG H , et al. Multicenter randomized double-blind phase Ⅲ trial of donafenib in progressive radioactive iodine-refractory differentiated thyroid cancer [J ] . Clin Cancer Res , 2023 , 29 ( 15 ): 2791 - 2799 .

XIA W , JIE W . ZEB1-AS1/miR-133a-3p/LPAR3/EGFR axis promotes the progression of thyroid cancer by regulating PI3K/AKT/mTOR pathway [J ] . Cancer Cell Int , 2020 , 20 : 94 . DOI: 10.1186/s12935-020-1098-1 http://doi.org/10.1186/s12935-020-1098-1

LASOLLE H , SCHIAVO A , TOURNEUR A , et al. Dual targeting of MAPK and PI3K pathways unlocks redifferentiation of Braf -mutated thyroid cancer organoids [J ] . Oncogene , 2024 , 43 : 155 - 170 .

XU Q Q , WANG J Q , MAO Y T , et al. Combined BRAF and PIM1 inhibitory therapy for papillary thyroid carcinoma based on BRAF V600E regulation of PIM1: synergistic effect and metabolic mechanisms [J ] . Neoplasia , 2024 , 52 : 100996 .

WEN S S , WU Y J , WANG J Y , et al. BRAFV600E/p-ERK/p-DRP1(Ser616) promotes tumor progression and reprogramming of glucose metabolism in papillary thyroid cancer [J ] . Thyroid ® , 2024 , 34 ( 10 ): 1246 - 1259 .

KLOOS R T , RINGEL M D , KNOPP M V , et al. Phase Ⅱ trial of sorafenib in metastatic thyroid cancer [J ] . J Clin Oncol , 2009 , 27 ( 10 ): 1675 - 1684 .

BARBARO D , FORLEO R , PROFILO M A , et al. Neoadjuvant treatment with lenvatinib and pembrolizumab in a BRAF V600E-mutated anaplastic thyroid cancer: a case report [J ] . Front Endocrinol (Lausanne) , 2024 , 15 : 1389294 .

FRENCH J , HAUGEN B , WORDEN F , et al. Combination targeted therapy with pembrolizumab and lenvatinib in progressive, radioiodine-refractory differentiated thyroid cancers [J ] . Clin Cancer Res , 2024 , 30 ( 17 ): 3757 - 3767 .

PINHEIRO NETO A , LUCCHESI H L , VALSECCHI V A D S , et al. Immunotherapy for patients with thyroid cancer: a comprehensive appraisal [J ] . Chin Clin Oncol , 2024 , 13 ( 3 ): 36.

KLEINENDORST S C , OOSTERWIJK E , BUSSINK J , et al. Combining targeted radionuclide therapy and immune checkpoint inhibition for cancer treatment [J ] . Clin Cancer Res , 2022 , 28 ( 17 ): 3652 - 3657 . DOI: 10.1158/1078-0432.CCR-21-4332 http://doi.org/10.1158/1078-0432.CCR-21-4332

WANG Z Q , WANG B J , CAO X T . Epigenetic checkpoint blockade: new booster for immunotherapy [J ] . Signal Transduct Target Ther , 2021 , 6 ( 1 ): 281.

MIAO Y Q , XU H , WANG S . PartIES: a disease subtyping framework with partition-level integration using diffusion-enhanced similarities from multi-omics Data [J ] . Brief Bioinform , 2024 , 26 ( 1 ): bbae609.

ALVES L F , DA SILVA I N , DE MELLO D C , et al. Epigenetic regulation of DLK1-DIO3 region in thyroid carcinoma [J ] . Cells , 2024 , 13 ( 12 ): 1001.

LECHNER M G , BRENT G A . A new twist on a classic: enhancing radioiodine uptake in advanced thyroid cancer [J ] . Clin Cancer Res , 2024 , 30 ( 7 ): 1220 - 1222 .

READ M , BROOKES K , ZHA L , et al. Combined vorinostat and chloroquine inhibit sodium-iodide symporter endocytosis and enhance radionuclide uptake in vivo [J ] . Clin Cancer Research , 2024 , 30 ( 7 ): 1352 - 1366 .

ZHAO Z Y , HERMAN J G , BROCK M V , et al. Methylation of DACT2 promotes papillary thyroid cancer metastasis by activating Wnt signaling [J ] . PLoS One , 2014 , 9 ( 11 ): e112336.

NILUBOL N , MERKEL R , YANG L , et al. A phase Ⅱ trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin [J ] . Clin Endocrinol (Oxf) , 2017 , 86 ( 1 ): 128 - 133 .

ZHANG G Q , XI C , JU N T , et al. Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer [J ] . J Endocrinol Invest , 2024 , 47 ( 8 ): 1953 - 1969 . DOI: 10.1007/s40618-023-02294-y http://doi.org/10.1007/s40618-023-02294-y

LI X R , LIU Y , LIU J , et al. STAG2 inactivation reprograms glutamine metabolism of BRAF -mutant thyroid cancer cells [J ] . Cell Death Dis , 2023 , 14 ( 7 ): 454.

HUO N , CONG R , SUN Z J , et al. STAT3/LINC00671 axis regulates papillary thyroid tumor growth and metastasis via LDHA -mediated glycolysis [J ] . Cell Death Dis , 2021 , 12 ( 9 ): 799.

HOU X K , SHI X L , ZHANG W , et al. LDHA induces EMT gene transcription and regulates autophagy to promote the metastasis and tumorigenesis of papillary thyroid carcinoma [J ] . Cell Death Dis , 2021 , 12 ( 4 ): 347.

MARTINELLI E , TROIANI T , D’AIUTO E , et al. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells [J ] . Int J Cancer , 2013 , 133 ( 9 ): 2089 - 2101 . DOI: 10.1002/ijc.28236 http://doi.org/10.1002/ijc.28236

LI A M , ZHANG R B , ZHANG Y C , et al. BEZ235 increases sorafenib inhibition of hepatocellular carcinoma cells by suppressing the PI3K/AKT/mTOR pathway [J ] . Am J Transl Res , 2019 , 11 ( 9 ): 5573 - 5585 .

LIU J J , LIU R Y , SHEN X P , et al. The genetic duet of BRAF V600E and TERT promoter mutations robustly predicts loss of radioiodine avidity in recurrent papillary thyroid cancer [J ] . J Nucl Med , 2019 , 61 : 177 - 182 .

SMALLRIDGE R C , CHINDRIS A M , ASMANN Y W , et al. RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-type papillary thyroid carcinoma [J ] . J Clin Endocrinol Metab , 2014 , 99 ( 2 ): E338-E347.

SUBBIAH V , HU M I , MANSFIELD A S , et al. Pralsetinib in patients with advanced/metastatic rearranged during transfection ( RET )-altered thyroid cancer: updated efficacy and safety data from the ARROW study [J ] . Thyroid ® , 2024 , 34 ( 1 ): 26 - 40 .

HU M T , SHI X-K , SONG P X . Collaborative inference for treatment effect with distributed data-sharing management in multicenter studies [J ] . Stat Med , 2024 , 43 ( 11 ): 2263 - 2279 .

QU J , WANG Y , XIONG C X , et al. In vivo gene editing of T-cells in lymph nodes for enhanced cancer immunotherapy [J ] . Nat Commun , 2024 , 15 ( 1 ): 10218.

HWANG E , KRUHLAK M , WONG N , et al. Attenuation of aggressive tumor progression of anaplastic thyroid cancer by p53 [J ] . Am J Cancer Res , 2024 , 14 ( 9 ): 4429 - 4444 . DOI: 10.62347/KXJJ8824 http://doi.org/10.62347/KXJJ8824

READ M L , BROOKES K , ZHA L , et al. Combined vorinostat and chloroquine inhibit sodium iodide symporter endocytosis and enhance radionuclide uptake in vivo [J ] . Clin Cancer Res Off J Am Assoc Cancer Res , 2023 , 30 : 1352 - 1366 .

ZHANG K , WANG J Y , HE Z Y , et al. Epigenetic targets and their inhibitors in thyroid cancer treatment [J ] . Pharmaceuticals (Basel) , 2023 , 16 ( 4 ): 559.

FU H , HUANG J X , SUN L , et al. FAP-targeted radionuclide therapy of advanced radioiodine-refractory differentiated thyroid cancer with multiple cycles of 177 Lu-FAPI-46 [J ] . Clin Nucl Med , 2022 , 47 ( 10 ): 906 - 907 .

CHEN Y , ZANG J , WU Z N , et al. 68 Ga-FAPI-RGD PET/CT detected skull metastasis better than 18 F-FDG in a patient with radioiodine-refractory differentiated thyroid cancer [J ] . Clin Nucl Med , 2024 , 49 ( 10 ): 964 - 965 .

HELISCH A , KRATOCHWIL C , KLEIST C , et al. Feasibility, tolerability, and preliminary clinical response of fractionated radiopharmaceutical therapy with 213 Bi-FAPI-46: pilot experience in patients with end-stage, progressive metastatic tumors [J ] . J Nucl Med , 2024 , 65 ( 12 ): 1917 - 1922 .

BORGONJE P E , ANDREWS L M , VAN DEN BRAND J G , et al. [ 68 Ga ] Ga-FAPI-46 PET/CT as an early indicator of complete remission in a patient treated with pembrolizumab for stage Ⅳ NSCLC [J ] . Eur J Nucl Med Mol Imaging , 2024 .

OSTROMINSKI J W , YADA R C , SATO N , et al. CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes [J ] . Stem Cells Transl Med , 2020 , 9 ( 10 ): 1203 - 1217 .

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