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

Award Number: R01DK133325
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/25/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $420,970 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	4	5/7/2025	NON-COMPETING CONTINUATION	$426,428
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	2	5/23/2025	NON-COMPETING CONTINUATION	-$23,971
2025	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	3	5/23/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$23,971
2025	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$99,542
2025	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	2/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	4/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/24/2025	NON-COMPETING CONTINUATION	-$105,000
														Subtotal = $420,970

Issue Date FY: 2024 ( Subtotal = $407,700 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/22/2024	NON-COMPETING CONTINUATION	$407,700
														Subtotal = $407,700

Issue Date FY: 2023 ( Subtotal = $439,774 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/24/2023	NEW	$439,774
														Subtotal = $439,774

Grand Total All Awards = $1,268,444

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

Award Number: R01DK133325

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/25/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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