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

用于研究和治疗库欣病的新型垂体腺瘤类器官模型的开发和标准化

• 批准号: 10656854
• 负责人: Andrew Scott Little
• 金额: $ 43.98万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-25 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656854
• 关键词: Acceleration; Adrenal Glands; Anxiety; Arizona; Automobile Driving; BRAF gene; Biochemical; CDH23 gene; Cardiovascular Diseases; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Lineage; Cells; Cellular biology; Cessation of life; Chemicals; Chronic; Clinic; Confocal Microscopy; Corticotropin; Data; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Disease; Disease remission; Drug Screening; Endocrine System Diseases; Endocrinologist; Exhibits; Exposure to; Flow Cytometry; Funding; Genes; Goals; Growth; Health; Hormone secretion; Human; Hydrocortisone; Hypopituitarism; Immune; In Vitro; Lead; Link; Malignant Neoplasms; Medical; Mental Depression; Modeling; Molecular Profiling; Morphology; Mus; Mutation; Neuroendocrine Tumors; Neurologic; Neurosurgeon; Obesity; Operative Surgical Procedures; Organoids; Pathogenesis; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pituitary Diseases; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Population; Positioning Attribute; Pre-Clinical Model; Production; Proliferating; Quality of life; Radiosurgery; Rattus; Recurrence; Recurrent disease; Recurrent tumor; Research; Resected; Resistance; Risk; Route; Signal Pathway; Standardization; Stroke; Stromal Cells; Study models; Surgeon; Technology; Therapeutic; Time; Tissues; Training; Translating; Tumor Pathology; Tumor Subtype; Tumor-Derived; USP8 gene; Universities; adenoma; clinical practice; digital; drug repurposing; effective therapy; experience; follow-up; illness length; improved; induced pluripotent stem cell; mortality risk; nano-string; novel; novel therapeutic intervention; patient tolerability; prevent; response; screening; standard of care; stem; stem cells; targeted treatment; therapy development; three dimensional cell culture; tissue/cell culture; transcriptome; transcriptomics; tumor

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.

项目概要/摘要 库欣病（CD）是一种严重的内分泌疾病，以促肾上腺皮质激素为特征 (ACTH) 分泌 PitNET，随后刺激肾上腺过度产生皮质醇。慢性的 接触过量的皮质醇会对健康产生广泛的有害影响，包括增加中风率、 糖尿病、肥胖、抑郁、焦虑和死亡。尽管 CD 与罹患此病的风险增加三倍有关 死亡，目前的护理医学治疗标准缺乏进步。目前的治疗表现出低 疗效和患者的耐受性。缺乏复制复杂性的临床前模型 腺瘤组织阻碍了我们开发直接针对肿瘤的有效疗法。这 CD 的一线治疗是垂体手术。在经验丰富的外科医生手中，肿瘤会复发 在 10 年的随访期间，多达 30% 至 50% 的患者出现这种情况。尽管多次治疗， 大约 50% 的患者未实现生化控制，这表明在常规临床实践中， 相当数量的克罗恩病患者并未达到初始和长期的疾病缓解。因此，医学 在以下情况下通常会考虑治疗： 当手术有禁忌症或无法达到手术目的时 缓解，或明显手术缓解后复发。虽然立体定向放射外科治疗 不完全切除或复发的 PitNET，主要缺点包括缓解时间较长和 垂体功能减退症的风险。疾病持续时间和可逆性之间存在反比关系 与 CD 相关的并发症，因此强调了早期针对垂体腺瘤的重要性。 开发新疗法的主要障碍是缺乏人类相关的先进体外肿瘤 模型。垂体细胞系不能复制 PitNET 的多细胞复杂性。在这种情况下，总体 目标是开发 PitNET 类器官，以增进我们对疾病发病机制和治疗的理解 CD 患者的垂体肿瘤。通过双方共同努力，最终目标一定能顺利实现 亚利桑那大学 (UA) 和巴罗神经病学研究所 (BNI) 将利用 接受过免费领域培训的专业人员，包括垂体的手术治疗、病理学和细胞生物学 疾病、类器官技术和高通量数据分析，包括挖掘筛选、分子分析、 和转录组学。这导致我们制定了具体目标：1）使用人类 PitNET 衍生的类器官来定义 CD 中促肾上腺皮质激素肿瘤亚型的分子特征，以及 2) 使用垂体肿瘤类器官作为 加速 CD 患者靶向治疗的临床前模型。资助期结束后， 我们将致力于实施与患者相关的类器官，以加速开发以下疗法： 将有效针对 CD 患者中分泌 ACTH 的垂体腺瘤。