Improved Diagnosis and Treatment of Cushing's Disease

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Sporadic pituitary adenomas are one of the most common human pathologies, found in more than 10% of the general population. Pituitary adenomas are mutationally bland and the pathogenic mechanisms underlying a vast majority of adenomas remains unknown. My group focuses on Cushings disease (CD) as a model to understand the pathogenic mechanisms underlying all sporadic pituitary adenomas. Due to the log amplification effect of ACTH on adrenal glands, when diagnosed, CD adenomas are often small (<1cm, microadenomas), minimally distort the pituitary architecture and have a predictable effect of the hormonal axes (biochemical testing confirms the presence of and remission from CD). Genomic sequencing discovered recurrent somatic mutations in the USP8 (30%), USP48 and BRAF genes (total 40%). Epigenetic dysregulation is hypothesized to underlie the rest - a majority of pituitary adenomas. Current studies attempt to study epigenomic mechanisms underlying sporadic adenomas by comparing the transcriptome of adenomas with each other or with allogenic autopsy derived pituitary glands. The transcriptome of intra-vital human pituitary gland is unknown, precluding identification of differential transcriptomic pathways in pituitary pathology. There exist no animal models, patient derived xenograft models or cell lines to investigate the pathogenesis of sporadic pituitary adenomas. We hypothesized that the normal human pituitary gland transcriptome will help us discover previously unknown pathogenic mechanisms that underlie sporadic adenomas. We discovered that although corticotropinomas are benign tumors, they undergo metabolic reprogramming much like malignant cancers. We found that metabolic reprogramming is mediated via isozyme switching of Hexokinase-1 (HK-1) to HK-2, lactate dehydrogenase A (LDH-A) to LDH-B and by nuclear targeting of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). We found that human corticotropinomas overexpress glucose transporter 1 (GLUT1) that allows increased uptake of glucose. We then demonstrated that GLUT1 expression can be transcriptionally modulated by stimulation with secretagogues such as corticotropin releasing hormone (CRH). We have translated these findings to improve FDG-PET detection (a marker of glucose uptake) of corticotropinomas (NIH Protocol 12-N-0007).5 We found that CRH stimulation led to increased mean FDG uptake in adenomas. Frequently, these tumors are invisible on MRI imaging. With CRH stimulation, blinded neuroradiologists were able to detect 40% of MRI invisible pituitary adenomas on PET imaging. Based on these data, we are now initiating a clinical trial to investigate the role of DDAVP stimulated PET imaging on detecting MRI negative pituitary adenomas that cause CD. We showed that corticotropinomas rely on glucose and the glycolytic pathway for survival. We then found that by using drugs that specifically target GLUT1 expression in tumors (such as a histone deacetylase inhibitor- vorinostat), we were able to decrease survival and hormone secretion in human corticotropinomas ex-vivo. Normally, ACTH secretion is modulated by promoter activation of the POMC gene by a heterodimer of retinoic receptor (RXR) and liver X receptor (LXR). We found vorinostat transcriptionally downregulated LXR selectively in murine tumor cells in-vitro but not in normal corticotrophs. Based on these findings, we have now initiated an FDA approved clinical trial of oral vorinostat in patients with CD to test its efficacy in normalizing hormone levels pre-operatively. Using the large clinical dataset of CD patients that is uniquely available at NIH, we developed a critical insight that the post-operative state represents an endogenous stress test. This insight now allows clinicians to predict hormonal remission after surgery for CD from just one post-operative serum hormone data point. We have now completed a trial where we measured stress hormone levels as the patients were waking up from surgery (emergence from anesthesia). We found that these data points were exquisitely sensitive in detecting the need for stress hormone replacement in our patients. Successful pre-operative imaging of millimeter sized pituitary adenomas can lead to improved surgical outcomes in CD. We are advancing imaging to help detect these adenomas. We have initiated and are currently continuing a first-in-human clinical trial to utilize an intracavitary MRI coil that is used during surgery for pituitary adenomas. Preliminary data analysis from this trial suggests that this coil can detect previously MRI negative pituitary adenomas.