晚期分化型甲状腺癌的分子靶向治疗

随着针对分化型甲状腺癌研究的深入,其特征性的分子分型和信号转导通路得以揭示,从而促进了分子靶向治疗的发展。对于放射性碘治疗失败的分化型甲状腺癌,索拉非尼和乐伐替尼等针对血管内皮生长因子通路的多靶点抑制剂被证明具有明显的抗肿瘤活性。此外,其他选择性的单靶点抑制剂以及促放射性碘摄取药物均显示出一定的治疗效果,而个体化的基因检测将为未来个体化的分子靶向治疗奠定基础。     

碘难治性分化型甲状腺癌靶向治疗新进展

近年来，靶向治疗为碘难治性分化型甲状腺癌带来了革命性的突破。新型靶向药物的研发，让更多晚期分化型甲状腺癌患者获得了更好的生存。以索拉非尼和仑伐替尼为代表的多靶点小分子酪氨酸激酶抑制剂显著提升了患者的无进展生存期。与此同时，靶向BRAF及靶向RET的新型酪氨酸激酶抑制剂同样也取得了瞩目的疗效，丰富了甲状腺癌的治疗手段。本文就靶向治疗在碘难治性分化型甲状腺癌中的最新研究进展进行综述。     

131I难治性分化型甲状腺癌的再分化治疗

¹³¹I难治性分化型甲状腺癌(radioiodine-refractory differentiated thyroid cancer,RR-DTC)是目前甲状腺癌临床治疗领域的一大难题。维甲酸类药物、过氧化物酶体增殖物激活受体激动剂、DNA甲基化酶抑制剂及组蛋白脱乙酰化酶抑制剂都曾被用于诱导RR-DTC再分化并与¹³¹I联合治疗,但疗效并不显著。近年来,随着对RR-DTC分子机制认识的不断深入,靶向治疗等新的再分化治疗策略越来越多地被尝试用于治疗RRDTC。相比之下,分子靶向药物用于诱导RR-DTC重摄碘及介导¹³¹I治疗效果较好,可能具有良好的应用前景。     

碘难治性分化型甲状腺癌诱导再分化治疗研究进展

分化型甲状腺癌（DTC）大多进展缓慢,经手术、促甲状腺素抑制治疗和（或）放射性碘（RAI）等规范化治疗后总体预后好,但仍有部分患者治疗后出现复发或远处转移,并可能在自然病程或治疗过程中丧失摄碘能力,不能从后续RAI治疗中获益,成为碘难治性分化型甲状腺癌（RAIRDTC）。RAIR-DTC患者可选择的治疗方法有限,且效果欠佳。近年来,随着对RAIR-DTC分子机制研究的不断深入,诱导再分化联合RAI治疗在RAIR-DTC中展现出一定的应用前景。本文综述了信号通路抑制剂、组蛋白去乙酰化酶抑制剂（HDACi）、DNA甲基化酶抑制剂、维甲酸类药物及过氧化物酶体增殖物激活受体（PPAR）激动剂在RAIR-DTC诱导再分化治疗中的进展。     

放射性~(131)I照射与分化型甲状腺癌细胞摄碘(~(125)I)率关系的实验研究

目的:探讨分化型甲状腺癌培养细胞接受放射性碘(131I)照射剂量与摄取放射性碘间的相关性,为放射性碘去除治疗甲状腺癌提供新的思路。方法:设两个实验组,对分化型甲状腺癌细胞进行培养,其一应用同一活度(20μCi)的放射性131I对培养细胞进行不同时间的照射,另组应用不同活度的放射性131I对培养细胞进行相同时间(12h)的照射,分别测定两组甲状腺癌细胞摄取放射性125I水平。结果:不同活度或不同时间的放射性131I照射使甲状腺癌细胞摄取碘的水平降低,受照射组与未照射对照组细胞摄碘率比较有显著性差异(P<0.01)。结论:放射性131I照射可以使分化型甲状腺癌细胞摄碘率显著降低。     

放射性131Ⅰ照射与分化型甲状腺癌细胞摄碘(125Ⅰ)率关系的实验研究

目的:探讨分化型甲状腺癌培养细胞接受放射性碘(131I)照射剂量与摄取放射性碘间的相关性,为放射性碘去除治疗甲状腺癌提供新的思路.方法:设两个实验组,对分化型甲状腺癌细胞进行培养,其一应用同一活度(20μCi)的放射性131I对培养细胞进行不同时间的照射,另组应用不同活度的放射性131I对培养细胞进行相同时间(12h)的照射,分别测定两组甲状腺癌细胞摄取放射性125I水平.结果:不同活度或不同时间的放射性131I照射使甲状腺癌细胞摄取碘的水平降低,受照射组与未照射对照组细胞摄碘率比较有显著性差异(P＜0.01).结论:放射性131I照射可以使分化型甲状腺癌细胞摄碘率显著降低.     

碘难治性甲状腺癌的诊治进展

多数分化型甲状腺癌(differentiated thyroid cancer,DTC)经过规范的手术、选择性131I治疗及促甲状腺激素抑制治疗后预后良好,然而,仍有部分转移性DTC的患者在早期或131I治疗过程中失去了摄碘能力发展为碘难治性DTC(radioiodine-refractory DTC,RAIR-DTC)。RAIR-DTC病情进展快,死亡率高,为这些患者寻找有效的治疗手段一直是甲状腺癌领域研究的热点。该文对碘难治性甲状腺癌的诊断及治疗进展进行综述,为及早识别这些患者,并为其他可能获益的治疗手段如靶向治疗及放疗等的早期干预争取时间。     

放射性^131I照射与分化型甲状腺癌细胞摄碘（^125I）率关系的实验研究

目的：探讨分化型甲状腺癌培养细胞接受放射性碘（^131I）照射剂量与摄取放射性碘间的相关性,为放射性碘去除治疗甲状腺癌提供新的思路.方法：设两个实验组,对分化型甲状腺癌细胞进行培养,其一应用同一活度（20μCi）的放射性^131I对培养细胞进行不同时间的照射,另组应用不同活度的放射性^131I对培养细胞进行相同时间（12h）的照射,分别测定两组甲状腺癌细胞摄取放射性^125I水平.结果：不同活度或不同时间的放射性^131I照射使甲状腺癌细胞摄取碘的水平降低,受照射组与未照射对照组细胞摄碘率比较有显著性差异（P＜0.01）.结论：放射性^131I照射可以使分化型甲状腺癌细胞摄碘率显著降低.     

甲状腺癌分子靶向治疗进展

目的：总结近年来国内外甲状腺癌分子靶向治疗方面的进展。方法：应用Medline及CHKD期刊全文数据库，以“甲状腺癌和分子靶向治疗”等为关键词检索2002—01～2007-10相关甲状腺癌分子靶向治疗的文献。对资料进行初选，选择甲状腺癌发病分子机制、分子靶向治疗药物作用机制、治疗效果和毒副反应评价方面的文献。纳入标准：1）甲状腺癌分子病因学研究；2）甲状腺癌分子靶向治疗药物作用机制研究；3）甲状腺癌分子靶向治疗疗效评价的研究；4）甲状腺癌分子靶向治疗发展方向的研究。粗选有近百篇关于甲状腺癌分子靶向治疗方面的文章，根据纳入标准，精选42篇文献，最后纳入分析22篇文献。结果：小分子多靶点酪氨酸激酶抑制剂范得他尼治疗晚期甲状腺髓样癌，索拉非尼治疗晚期甲状腺乳头状癌，羟胺类口服组蛋白去乙酰酶抑制剂SAHA治疗晚期甲状腺癌均取得一定效果，利用选择性COX-2抑制剂塞来昔布治疗晚期分化型甲状腺癌未取得满意疗效。而更多的，1名床实验如AMG706治疗分化型甲状腺癌和甲状腺髓样癌以及利用伊马替尼治疗甲状腺未分化癌的，临床试验正在进行。结论：甲状腺癌分子靶向治疗显示出良好的前景，有望成为治疗的发展方向之一。     

儿童及青少年分化型甲状腺癌核医学诊治中国专家共识（2022年版）

儿童及青少年分化型甲状腺癌（differentiated thyroid carcinoma in children and adolescents,caDTC）与成人存在较大差异,用于指导成人甲状腺癌的指南及治疗策略不完全适用于儿童及青少年。因此,来自核医学科、甲状腺外科、内分泌科、超声科、病理科及分子生物等甲状腺领域的专家组成编委会共同参与针对儿童及青少年人群的分化型甲状腺癌诊治共识的编撰。本共识的制定基于实用性、本土性及治疗手段可及性的原则,内容包括caDTC的流行病学、检查手段、治疗策略（手术、放射性碘、靶向及内分泌治疗）及随访等,基本涵盖caDTC的常见临床管理。     

Anaplastic thyroid cancer: a comprehensive review of novel therapy

Thyroid carcinomas are the most common cancer of the human endocrine system and are typically classified as papillary, follicular, anaplastic or medullary carcinomas. Although epidemiological studies have suggested an increased incidence of anaplastic thyroid carcinomas (ATCs) worldwide, there has been little evidence to suggest that, with current treatment, there has been any improvement in patient survival over the past two decades. Anaplastic thyroid carcinoma is one of the most aggressive human malignancies and is responsible for a disproportionate number of thyroid cancer-related deaths. Currently, available therapy for ATCs includes: chemotherapy, radiotherapy and surgery. Due to the poor treatment outcomes for individuals diagnosed with ATCs who undergo conventional therapy, novel therapeutic strategies for the treatment of ATCs are urgently needed. In this article, we review the existing management of ATCs, with a focus on novel molecular-targeted approaches as described in preclinical studies and in early human clinical trials.     

PARP抑制剂用于铂敏感复发卵巢癌患者维持治疗的血液学毒性概述

卵巢癌是威胁女性健康和生命的重大疾病之一。近年来,聚腺苷二磷酸核糖聚合酶抑制剂[poly (ADP-ribose)polymerase inhibitors,PARPi]作为一类新型的靶向治疗药物为卵巢癌患者带来获益,并被国内外多项临床指南、规范推荐用于铂敏感复发卵巢癌患者的维持治疗及术后的维持治疗。但与此同时带来的安全性问题,尤其是血液学毒性值得关注。从作用机制、药代动力学出发,对比目前已上市的3种PARPi的特征及其血液学毒性差异,以期为复发性卵巢癌患者临床用药提供参考。     

The realisation of targeted antitumour therapy

Better understanding of the pathways regulating proliferation and metastasis of cancer cells has led to the development of novel molecular-targeted therapies. The number of molecular-targeted agents approved for use in the clinic is growing, with many more in clinical trials. Most of these compounds can be broadly classified into two main categories: monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The pathological processes targeted include vascular endothelial growth factor-dependent tumour angiogenesis and epidermal growth factor receptor-dependent tumour cell proliferation and survival. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. Recent progress in targeted antitumour therapy is discussed, with a focus on antiangiogenesis.     

Basic research for hormone-sensitivity of breast cancer

Hormonal therapy is a rapidly progressing molecular-targeted therapy for breast cancer, using drugs such as LH-RH agonists, SERMs and aromatase inhibitors. Basic research for estrogen signaling and hormone sensitivity in breast cancer cells strongly contributes to the progression of clinical treatment of breast cancer. However, further problems remain unresolved, for example the accurate prediction of individual response to each hormonal therapy. Moreover, novel combinations with other molecular-targeted therapies might be advance the effectiveness of hormonal therapies. To address these issues, we are developing several new tools such as focused microarray and a GFP-reporter cell system. We first identified estrogen-responsive genes by comprehensive expression profiling of estrogen receptor (ER)-positive breast cancer cells, and produced a custom-made estrogen-responsive microarray of a narrowed-down subset. Using this microarray, we studied several basic issues regarding estrogen signaling and expression analysis of estrogen-responsive genes in breast cancer tissues. Furthermore, expression of several candidate genes selected from the contents of the customarray was also analyzed by real-time RT-PCR and by immunohistochemical techniques, to find new predictive factors for responsiveness to hormone therapy for primary breast cancer patients. We found that the expression of several genes such as HDAC6 significantly correlated with disease-free and overall survival of ER-positive patients. Furthermore, we are developing a new tool for analyzing the estrogen-related microenvironment on individual breast cancer patients using ERE-GFP-indicator cells. This system enables visualization of tumor-stroma interactions and the effects of aromatase inhibitors in an individual breast cancer sample. We believe that these approaches could provide not only new clues to elucidate the estrogen-dependent mechanisms of cancer, but also clinical benefits to patients by predicting individual response to hormonal therapy.     

Investigational therapies for metastatic thyroid carcinoma

Although traditional chemotherapy has yielded disappointing results in the therapy of progressive metastatic thyroid cancer, the recent development of a wide range of novel therapies targeting critical steps in the pathogenesis of thyroid cancer has led to a renewed interest in thyroid cancer clinical trials. This review provides an overview of the pathogenesis of thyroid cancer with particular emphasis on specific molecular targets that can be modulated with these novel agents. The article reviews the results for the small number of thyroid cancer patients included in published therapeutic trials and critically examines patient selection criteria for inclusion in clinical trials. Given the dramatic increase in availability of thyroid cancer clinical trials, all patients with radioactive iodine-refractory, progressive metastatic thyroid cancer should be considered for inclusion in a novel therapy trial.     

New approaches for pancreatic cancer in Japan

Pancreatic cancer is the fifth leading cause of cancer-related mortality in Japan, with an estimated annual incidence rate of approximately 20,000 cases. Even in patients with resectable disease, the long-term outcome remains unsatisfactory due to early recurrence after resection. However, surgical resection has offered the only curative strategy for pancreatic cancer. Currently available chemotherapeutic agents have little impact on survival, although the development of gemcitabine has renewed interest in clinical research for pancreatic cancer. To further improve the prognosis of patients with pancreatic cancer, the development of more effective nonsurgical treatment is essential. Studies to identify more effective treatments, such as chemotherapy, interventional therapy and gene therapy, are ongoing in Japan. The expanding understanding of molecular and genetic biology should facilitate research to develop novel molecular-targeted agents and to establish individualized therapy regimens for this disease.     

Molecular-targeted therapy

This article reviews the concept of molecular-targeted therapy and the current development status of molecular-targeted agents for lung cancer. Epidermal growth factor receptor inhibitors have shown promising antitumor activity against cisplatin-resistant non-small cell lung cancer in phase II trials. Appropriate clinical evaluation of these agents and collaboration with basic researchers are essential for further development.     

Advances in the biology of lung cancer chemoprevention.

The heavy burden of lung cancer, which includes the highest worldwide mortality of any cancer, and its resistance to standard approaches (smoking cessation, screening, and therapy), have motivated an intense interest in chemoprevention of this disease. Randomized controlled trials of agents (including retinoids, beta-carotene, and vitamin E) to prevent lung cancer have produced only disappointing clinical results to date. New, molecular-targeted approaches are advancing rapidly, however, with many promising targets and interactive signaling pathways for developing novel agents and combinatorial approaches in this setting. This promise is illustrated by recent studies of 15-hydroxyprostaglandin dehydrogenase, which plays a critical role in polyunsaturated fatty acid metabolism and (like another important target, prostacyclin) is downstream of cyclooxygenase-2. 15-hydroxyprostaglandin dehydrogenase degrades prostaglandin E(2), appears to have tumor suppressor activity, and can be induced both by peroxisome proliferator-activated receptor-gamma ligands and an epidermal growth factor receptor inhibitor. Other important targets/pathways include the insulin-like growth factor axis, phosphoinositide 3-kinase pathway, cyclin D and E family members, and epigenetic events. Defining highest lung cancer risk (eg, establishing molecular risk models through long-term analyses of high-risk cohorts) will facilitate the clinical development of molecular-targeted prevention that will potentially reduce the enormous burden of lung cancer.     

p16 Methylation is associated with chemosensitivity to fluorouracil in patients with advanced gastric cancer

Thyroid cancer (TC) is the most common endocrine malignancy with steadily increasing incidence over the past few decades. Although standard strategies for the management of TC offer optimal outcomes in TC patients with favorable histological types at early stage, challenges arising from diagnosis and therapy still exist during clinical practice. A number of genetic alterations have been described in thyroid cancer, which provides an unprecedented opportunity for the identification of novel diagnostic and prognostic molecular markers as well as novel therapeutic targets. Molecular-targeted therapies, which have been investigated recently with increasing success, may prove to be a breakthrough in patients with advanced, radioiodine-refractory thyroid cancers. This review summarizes the latest progression in molecular diagnosis and targeted therapy of TC.