Advancing Targeted Therapies for Cushing's Disease Using Pituitary Neuroendocrine Tumor Organoids - 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 first-line treatment for CD is pituitary surgery. In the hands of an experienced surgeon, tumor recurrence occurs in as many as 56% 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. Our research team has published data demonstrating that organoids derived from corticotroph type PitNETs consist of differentiated cell lineages, stem/progenitor cells, and immune and stromal cells that replicate much of the patient’s own tumor pathology, function, and genetic alterations. Our team’s expertise in organoid technology has enabled the first successful development and implementation of this advanced 3D culture in the much-needed PitNET research arena. Using human PitNET organoids we have revealed stem and progenitor cell populations that express an antioxidant mechanism that may be targeted to prevent tumor recurrence and medical- and radiation-therapy resistance develop Specific Aims: 1) Take a noncommittal research approach to define the molecular . This led us to signatures of corticotroph tumor subtypes in CD, and 2) Leverage the complementary value of the human hypothalamic- pituitary-adrenal (HPA) Axis-On-A-Chip and the canine naturally occurring CD model to accelerate targeted therapies for patients with CD. The objectives will be successfully achieved by collaborative efforts between the University of Arizona (UA), Barrow Neurological Institute (BNI), University of Georgia Athens (UGA) that will leverage the expertise of professionals trained in complimentary fields including surgical treatments, pathology and cell biology of pituitary disease, organoid technology, canine preclinical in vitro and in vivo models and high throughput data analysis including dug screening, molecular profiling, and transcriptomics. 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.
