1型多发性内分泌肿瘤的新疗法?

Hessa Boharoon, Ashley Grossman
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摘要

胰腺神经内分泌肿瘤(pNETs)是多发性1型内分泌瘤(MEN1)的主要表现,是该疾病发病率和死亡率的最重要原因。有一些证据表明,早期使用生长抑素类似物可以延缓进展,特别是小的无功能肿瘤,但没有其他预防治疗的患者,转移性疾病的治疗与散发性pNETs相似。最近的一项研究表明,在细胞系和动物模型中,MEN1突变导致二氢酸脱氢酶(DHODH)的上调,该酶参与嘧啶合成的前体代谢物的增加。在这些研究中,通过各种手段(包括DHODH抑制剂来氟米特)阻断这一途径,可以减缓细胞生长和肿瘤进展,这表明men1突变组织特异性依赖DHODH。在3例MEN1和pNETs患者的初步临床研究表明,该药物具有一定的治疗潜力,该药物先前已用于类风湿关节炎患者数年。建议进一步的临床试验,以评估其治疗MEN1和pNETS患者的潜力。本文描述了MEN1和pNETs的临床问题,并回顾了最近关于这些初步结果的出版物报道。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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A New Medical Therapy for Multiple Endocrine Neoplasia Type 1?

Pancreatic neuroendocrine tumours (pNETs) are a major manifestation of multiple endocrine neoplasia type 1 (MEN1), and the most significant cause of morbidity and mortality in this disorder. There is some evidence that the early use of somatostatin analogues can retard progression, especially of small non-functioning tumours, but there are no other prophylactic therapies for patients, and the treatment of metastatic disease is similar to that for sporadic pNETs. A recent study has shown that in cell line and animal models, MEN1 mutations lead to an upregulation of the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in increasing precursor metabolites for the synthesis of pyrimidines. In these studies, blockade of this pathway by various means, including the DHODH inhibitor leflunomide, attenuates cell growth and tumour progression, suggesting a critical dependence on DHODH specifically in MEN1-mutated tissue. Preliminary clinical studies in three patients with MEN1 and pNETs have indicated some therapeutic potential of this drug, which has previously been used for some years in patients with rheumatoid arthritis. It is suggested that further clinical trials of this re-purposed drug are indicated to evaluate its potential for the treatment of patients with MEN1 and pNETS. This article describes the clinical problem of MEN1 and pNETs, and reviews the recent publication reporting on these initial results.

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