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/文摘