Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer

Ruping LI; Hui YANG

doi:10.19401/j.cnki.1007-3639.2025.01.005

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Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer

Specialist' Commentary | 更新时间：2025-12-31

- Current status and future prospects of clinical trials for radioiodine-refractory thyroid cancer
- China Oncology Vol. 35, Issue 1, Pages: 40-48(2025)
- 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：
- 基金信息：
  
  Henan Province Science and Technology Research Project(242102311045);National Natural Science Foundation of China(82402330);Henan Provincial Health Commission of China(LHGJ20240132)
- DOI：10.19401/j.cnki.1007-3639.2025.01.005
  CLC： R736.1
- Received：13 December 2024，
  
  Revised：2025-01-21，
  
  Published：30 January 2025
- 稿件说明：
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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：

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

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