R01DK138306

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.

University Of Georgia Research Foundation

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Arizona United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)