Cushing's disease: current medical therapies and molecular insights guiding future therapies
Cushing's disease: current medical therapies and molecular insights guiding future therapies
复制标题
DOI：
10.3171/2014.10.focus14700
复制
发表时间：
2015-02-01
影响因子：
4.1
通讯作者：
Aghi, Manish K.
中科院分区：
文献类型：
--
作者：
Lau, Darryl;Rutledge, Caleb;Aghi, Manish K.
库欣氏病（CD）可导致继发于激素后遗症或垂体瘤占位效应的严重发病率。经蝶入路切除分泌促肾上腺皮质激素（ACTH）的垂体腺瘤是一线治疗方法。然而，在患者无法接受手术、患有急性皮质醇增多症或疾病复发的情况下，药物治疗可以发挥重要作用。作者进行了系统的审查，以突出的CD的药物治疗的疗效，并讨论新的分子见解，可以指导未来的CD的药物治疗的发展。在确定CD的单个药物治疗剂后，对每种药物进行正式的系统检索。短语“（药物名称）和库欣”在PubMed中用作检索词，检索时间为2014年之前的所有年份。对每篇文章的摘要进行了综述，以了解评价CD药物治疗疗效的研究。只有研究，招募了至少20例患者被纳入review.RESULTS共11篇文章6个单独的代理商被纳入本次审查。根据作用水平对特定药物治疗进行分类：垂体导向（卡麦角林和帕瑞肽）、肾上腺/类固醇生成导向（酮康唑、甲吡酮和米托坦）和终末组织导向/皮质醇受体（米非司酮）。确定的研究包括回顾性综述和小型临床试验。只有帕瑞肽和米非司酮进行了III期临床试验，并获得FDA批准用于治疗CD患者。总体而言，发现靶向ACTH分泌和类固醇生成的药物在将尿游离皮质醇（UFC）降低至接近正常水平方面非常有效。在45%-100%的患者中观察到UFC显著降低，大多数患者获得临床改善。类似地，在终末组织水平的抑制导致87%的患者的临床改善。然而，与这些药物相关的副作用率很高（高达88%）。酮康唑已被证明可以增强肿瘤在MRI上的表现，以促进垂体切除。已经确定了有前途的分子靶点，包括表皮生长因子受体、视黄酸受体和细胞周期蛋白依赖性激酶。这些途径已被链接到pro-opiomelanocortin的表达，ACTH分泌，和肿瘤growth.CONCLUSIONS尽管令人鼓舞的III期临床试验导致FDA批准2剂治疗CD患者，没有代理人尚未产生的结果相比，切除。因此，对CD发病机制的分子见解将需要继续扩展，直到它们可以导致CD的药物治疗的发展，具有良好的副作用特征和与切除术相当的疗效。理想情况下，这些药物还应该减少肿瘤大小，这可能会允许它们最终停药。
OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD.METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase "(name of agent) and Cushing's" was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review.RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%-100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth.CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.