Development and Standardization of a Novel Pituitary Adenoma Organoid Model for the Study and Treatment of Cushing's Disease

项目摘要/摘要 库欣病是一种以促肾上腺皮质激素为特征的严重内分泌疾病 促肾上腺皮质激素(ACTH)--分泌PitNET，随后刺激肾上腺过度产生皮质醇。慢性 暴露在过量皮质醇中对健康有广泛和有害的影响，包括中风发生率增加， 糖尿病、肥胖症、抑郁症、焦虑和死亡。尽管CD与增加三倍的风险有关 死亡，目前缺乏先进的护理标准的医疗治疗。目前的治疗方法显示出低水平 对患者的疗效和耐受性。临床前模型的缺乏复制了 腺瘤组织阻碍了我们开发直接针对肿瘤的有效治疗方法。这个 CD的一线治疗是脑下垂体手术。在经验丰富的外科医生手中，肿瘤复发 在10年的随访期内，多达30%到50%的患者。尽管进行了多种治疗， 大约50%的患者没有实现生化控制，这表明在常规临床实践中， 在相当数量的CD患者中，最初和长期的疾病缓解无法实现。因此，医疗 治疗通常在以下情况下考虑：当手术被禁忌或不能达到目的时 缓解，或在明显的手术缓解后复发。而立体定向放射外科治疗 不完全切除或复发的PTNETs的主要缺点包括缓解时间较长和 有垂体功能减退的风险。在病程和可逆性之间存在反向关系。 与CD相关的并发症，从而强调了早期靶向垂体腺瘤的重要性。 开发新的医学疗法的主要障碍是缺乏与人类相关的高级体外肿瘤 模特们。垂体细胞系不能复制PitNETs的多细胞复杂性。在这种情况下，总体上 目的是开发匹特-奈特有机化合物，以促进我们对其发病机制和治疗的认识。 CD患者的脑垂体瘤。总体目标将通过以下各方的合作努力成功实现 亚利桑那大学(UA)和巴罗神经研究所(BNI)将利用 受过免费培训的专业人员，包括外科治疗、病理和脑下垂体细胞生物学 疾病、有机物技术和高通量数据分析，包括DUG筛查、分子图谱、 还有转录本。这导致我们制定了具体的目标：1)使用人类Pitnet衍生的有机化合物来定义 CD中促肾上腺皮质细胞肿瘤亚型的分子特征；2)以垂体肿瘤细胞器为靶点 加快CD患者靶向治疗的临床前模式。在资助期结束时， 我们将定位于实施与患者相关的有机化合物，以加速开发 将有效靶向CD患者中分泌ACTH的垂体腺瘤。

PROJECT SUMMARY/ABSTRACT Cushing’s disease (CD) is a serious endocrine disorder characterized by an adrenocorticotropic hormone (ACTH)-secreting PitNET that subsequently stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has wide ranging and detrimental effects on health, including increased stroke rates, diabetes, obesity, depression, anxiety and death. Although CD is linked to a threefold increase in the risk of death, the advancement of current standard of care medical therapy is lacking. Current treatments exhibit low efficacy and tolerability for patients. The absence of preclinical models that replicate the complexity of the adenoma tissue has prevented us from developing effective therapies that are targeted to the tumor directly. The first-line treatment for CD is pituitary surgery. In the hands of an experienced surgeon, tumor recurrence occurs in as many as 30% to 50% of patients during the 10-year follow-up period. Despite multiple treatments, biochemical control is not achieved in approximately 50% of patients, suggesting that in routine clinical practice, initial and long-term disease remission is not achieved in a substantial number of CD patients . Hence, medical therapy is often considered in the following situations: when surgery is contraindicated or fails to achieve remission, or when recurrence occurs after apparent surgical remission. While stereotactic radiosurgery treats incompletely resected or recurrent PitNETs, the main drawbacks include the longer time to remission and the risk of hypopituitarism. There is an inverse relationship between disease duration and reversibility of complications associated with CD, thus emphasizing the importance of targeting the pituitary adenoma early. The primary barrier to developing new medical therapies is the lack of human relevant advanced in vitro tumor models. Pituitary cell lines do not reproduce the multicellular complexity of PitNETs. In this instance, the overall objective is to develop PitNET organoids to advance our understanding of the pathogenesis and treatment of pituitary tumors in CD patients. The overall goal will be successfully achieved by collaborative efforts between the University of Arizona (UA) and Barrow Neurological Institute (BNI) that will leverage the expertise of professionals trained in complimentary fields including surgical treatments, pathology and cell biology of pituitary disease, organoid technology and high throughput data analysis including dug screening, molecular profiling, and transcriptomics. This led us to develop Specific Aims: 1) To use human PitNET derived organoids to define the molecular signatures of corticotroph tumor subtypes in CD, and 2) To use the pituitary tumor organoids as a preclinical model to accelerate targeted therapies for patients with CD. At the completion of the funding period, we will be positioned to implement patient-relevant organoids to accelerate the development of therapies that will effectively target ACTH-secreting pituitary adenomas in patients with CD.