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.

项目摘要/摘要 库欣病（CD）是一种严重的内分泌疾病，其特征是肾上腺皮质激素激素 （ACTH） - 分泌PITNET，随后刺激肾上腺以产生过度生产皮质醇。慢性的 超过皮质醇的暴露对健康的范围和不利影响，包括中风率提高， 糖尿病，肥胖，抑郁，焦虑和死亡。尽管CD与增加的风险增加了三倍 死亡，目前的护理医疗疗法的进步。当前的治疗暴露低 患者的功效和耐受性。没有复制临床前模型的复杂性 腺瘤组织使我们无法开发直接针对肿瘤的有效疗法。 CD的一线治疗是熟悉的手术。在经验丰富的外科医生的手中，发生肿瘤复发 在10年的随访期内，多达30％至50％的患者中。尽管有多种治疗， 大约50％的患者未能实现生化控制，这表明在常规临床实践中， 在大量的CD患者中未实现初始和长期疾病的缓解。因此，医疗 在以下情况下通常考虑治疗：禁忌手术或无法实现治疗 缓解或在明显的手术缓解后发生复发时。而立体定向放射外科治疗 主要缺点不完整切除或复发性的凹痕，包括较长的缓解时间和 降低症的风险。疾病持续时间与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。 开发新医疗疗法的主要障碍是缺乏人类相关的晚期体外肿瘤 型号。垂体细胞系不会再现PITNET的多细胞复杂性。在这种情况下，总体 目的是开发PITNET器官，以促进我们对 CD患者中的型肿瘤。总体目标将通过合作努力成功实现 亚利桑那大学（UA）和巴罗神经学研究所（BNI）将利用专业知识 在免费领域接受培训的专业人员，包括垂体的手术治疗，病理学和细胞生物学 疾病，器官技术和高吞吐量数据分析，包括DUG筛查，分子分析， 和转录组学。这使我们发展了特定的目标：1）使用人pitnet衍生的器官来定义 CD中皮质营养肿瘤亚型的分子特征和2）将垂体肿瘤类器官用作A 临床前模型以加速CD患者的靶向疗法。在资金期结束时， 我们将有助于实施与患者相关的器官，以加速疗法的发展 将有效地靶向CD患者中分泌ACTH的垂体腺瘤。