Trim7 expression regulates the Wnt/b-catenin signaling pathway involved in the mechanism of drug resistance in prolactin adenoma DAs

The annual incidence of pituitary adenomas in the population is as high as 7.5-15/100,000 people, and pituitary prolactinoma (prolactinoma) is the most common pituitary adenoma with endocrine function, accounting for about 45-70% of all pituitary adenomas. With the improvement of people's health awareness and the advancement of diagnostic technology, imaging equipment, and surgical level, the number of actual patients diagnosed in clinic is significantly higher than the above The actual number of clinically diagnosed patients is significantly higher than the above data. Prolactin adenomas are often characterized by infertility, amenorrhea, and breast milk overflow in women due to hyperprolactinemia, decreased libido and sexual function and infertility in men, as well as symptoms of pressure including headache, vision loss, and visual field damage. These symptoms seriously affect patients' quality of life, and the number of deaths and disabilities associated with them has been increasing in recent years, placing a heavy burden on society and families.Currently, the main treatment for pituitary prolactin adenomas is drug therapy, and dopamine agonist (DAs) is the first choice for treatment, and the DAs used as the first-line drugs in clinical practice are bromocriptine and cabergoline, etc. The DAs can be used as a first-line drug to treat prolactin adenomas by interacting with the surface of the cell surface. DAs are able to inhibit PRL production and secretion and mediate tumor volume contraction by specifically binding to dopamine receptors on the cell surface of prolactin adenomas. However, there are still about 10-25% of patients who are insensitive to DAs, i.e., Dopamie agonist resistant prolactinomas (DARPs), in the current clinical treatment. Currently, there is no strict international definition of DARPs, but from the endocrine point of view, the main point of view is failure to normalize serum PRL levels. From an endocrine point of view, the definition of DARPs is failure to normalize serum PRL levels. In terms of tumor size reduction, it is generally defined as a failure to reduce tumor size by at least 50% with the maximum conventional dose of drugs (bromocriptine 15mg/d or cabergoline 3mg/wk) for at least 3 consecutive months. Currently about 17% of patients treated with cabergoline fail to reduce PRL levels to the normal range.Currently, in clinical practice, the main choice of non-pharmacologic treatment for patients with DARPs is surgery and radiation therapy. However, the results of surgical treatment in patients with DARPs are poor.Hamilton DK et al. reported that only 36% of 61 patients with DARPs after surgical treatment had normalized PRL levels after surgery [9]. Epidemiologic studies have shown that DARPs are more likely to invade the cavernous sinus, which is invaded by about 71% of DARPs, compared with only 10% of sensitive prolactinomas. Radiation therapy, such as Gamma Knife therapy, may be used for DARPs that are surgical remnants. Unfortunately, however, prolactinomas are the least sensitive functional pituitary adenomas to radiotherapy, with a 4-year PRL hormone remission rate of only 18%, and a remission rate of only 16% after gamma knife treatment. Therefore, surgical treatment and radiation therapy for DARPs remain ineffective and their clinical management is tricky.Therefore, as a supplement to the existing therapeutic regimens for DARPs, it is necessary to develop new therapeutic agents based on the mechanism of occurrence of DARPs. Decitabine (DAC) is a DNA methyltransferase (DNMT) inhibitor that induces DNA demethylation, enabling the restoration of key genes that are essential for cellular differentiation and proliferation, thereby exerting antitumor effects.

人群中垂体腺瘤（pituitary adenomas）的年发病率高达7.5~15例/10万人，而催乳素瘤（pituitary prolactinoma，prolactinoma）是最常见的功能性垂体腺瘤，约占所有垂体腺瘤的45%~70%。随着民众健康意识的提升，以及诊断技术、影像设备与外科诊疗水平的进步，临床实际确诊的患者数量已显著高于上述统计数据。
催乳素瘤患者常因高催乳素血症（hyperprolactinemia）出现女性不孕、闭经与溢乳，男性则表现为性欲减退、性功能障碍与不孕，同时还会伴随头痛、视力下降、视野缺损等压迫症状。此类症状严重降低患者的生活质量，近年来与之相关的死亡与残疾病例数持续攀升，给社会与家庭带来沉重负担。
当前催乳素瘤的主要治疗方式为药物治疗，多巴胺激动剂（dopamine agonist，DAs）为首选治疗药物，临床一线应用的DA类药物包括溴隐亭（bromocriptine）与卡麦角林（cabergoline）等。DA类药物可通过与催乳素瘤细胞表面的多巴胺受体特异性结合，抑制催乳素（prolactin，PRL）的合成与分泌，并介导肿瘤体积缩小，以此实现催乳素瘤的一线治疗。然而目前临床中仍有约10%~25%的患者对DA类药物不敏感，即多巴胺激动剂耐药催乳素瘤（dopamine agonist resistant prolactinomas，DARPs）。
目前国际上尚无针对DARPs的统一严格定义，但从内分泌学视角而言，主流观点认为其核心特征为血清PRL水平未能恢复至正常范围。在肿瘤体积缩小的评估维度，通常的定义为：连续3个月及以上使用最大常规剂量药物（溴隐亭15mg/d或卡麦角林3mg/周）治疗后，肿瘤体积未出现至少50%的缩小。当前约17%接受卡麦角林治疗的患者无法将PRL水平降至正常范围。
临床中针对DARPs患者的非药物治疗手段主要为手术与放射治疗，但手术治疗的疗效欠佳。Hamilton DK等学者的研究显示，61例接受手术治疗的DARPs患者中，仅36%在术后实现了PRL水平正常化[9]。流行病学研究表明，相较于仅10%的敏感型催乳素瘤，约71%的DARPs会侵袭海绵窦。对于手术残留的DARPs，可采用伽马刀等放射治疗手段，但遗憾的是，催乳素瘤是对放射治疗最不敏感的功能性垂体腺瘤类型：其4年PRL激素缓解率仅为18%，伽马刀治疗后的缓解率仅为16%。因此，针对DARPs的手术与放射治疗效果均不甚理想，临床管理极具挑战性。
因此，作为现有DARPs治疗方案的补充，亟需基于其发病机制开发新型治疗药物。地西他滨（Decitabine，DAC）是一种DNA甲基转移酶（DNA methyltransferase，DNMT）抑制剂，可诱导DNA去甲基化，使细胞分化与增殖所必需的关键基因恢复表达，从而发挥抗肿瘤活性。