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.

项目总结/摘要 库欣病（CD）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）-分泌PitNET，随后刺激肾上腺过度产生皮质醇。慢性 暴露于过量的皮质醇对健康具有广泛的有害影响，包括增加中风率， 糖尿病、肥胖、抑郁、焦虑和死亡。虽然CD与三倍的风险增加有关， 死亡，目前的医疗护理标准缺乏进步。目前的治疗表现出低 患者的疗效和耐受性。缺乏临床前模型来复制 腺瘤组织已经阻止我们开发直接针对肿瘤的有效疗法。的 CD的一线治疗是垂体手术。在经验丰富的外科医生手中， 在10年的随访期间，多达30%至50%的患者。尽管进行了多次治疗， 在大约50%的患者中没有达到生化控制，这表明在常规临床实践中， 在相当数量的CD患者中没有实现初始和长期的疾病缓解。因此，医疗 治疗通常在以下情况下考虑：当手术禁忌或无法实现 缓解或明显手术缓解后复发。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， 垂体功能减退的风险。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人类相关的晚期体外肿瘤治疗。 模型PITNETs细胞系不能复制PitNETs的多细胞复杂性。在这种情况下， 目的是开发PitNET类器官，以促进我们对 CD患者的垂体瘤。总体目标将通过以下方面的合作努力成功实现： 亚利桑那大学（UA）和巴罗神经病学研究所（BNI）将利用 在包括垂体外科治疗、病理学和细胞生物学在内的互补领域接受过培训的专业人员 疾病，类器官技术和高通量数据分析，包括Dug筛选，分子谱分析， 和转录组学。这使我们开发了具体目标：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细胞肿瘤亚型的分子特征，以及2）使用垂体瘤类器官作为 加速CD患者靶向治疗的临床前模型。在供资期结束时， 我们将定位于实施与患者相关的类器官，以加速治疗方法的开发， 将有效靶向CD患者的ACTH分泌性垂体腺瘤。