Improved Diagnosis and Treatment of Cushing's Disease

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Transsphenoidal surgery (TSS) is the best treatment for corticotrophin adenomas causing Cushing's Disease (CD). Although caused by benign pituitary tumors, CD can drastically affect the lives of patients suffering from the disease. Increased adrenocorticotropic hormone (ACTH) and resultant hyper-cortisolemia can lead to obesity, hypertension, hyper coagulability, morphologic changes and death. Successful TSS can provide immediate cure from CD while preserving endocrine function in around 70 - 80% of patients. The patients that do no achieve remission with TSS eventually undergo many treatments including radiation, and life-long cortisol suppression therapy. Success in TSS is directly linked to the ability to accurately detect pituitary tumors before surgery. Routine pituitary magnetic resonance imaging (MRI) fails in up to 50% of cases of CD in detecting CA tumors, presumably due to small size or poor MRI contrast to noise. When tumors are identifiable on MRI before surgery, the cure rates can reach 90%. When adenoma is not identified on imaging before surgery, exploratory surgery is much less successful in curing the patient, and in many cases, eventually leads to radiation therapy and panhypopituitarism. 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).13 We also posit that nuclear targeting of PFKFB3 provides a causal mechanism for downregulation of cell cycle inhibitor p27 in human corticotropinomas. 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). 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 (manuscript submitted). We showed that corticotropinomas rely on glucose and the glycolytic pathway for survival. Selective inhibition of HK-2 with 3-bromo-pyruvate led to significantly decreased glycolytic activity and cell survival specifically in human corticotropinomas while sparing the normal gland. We then found that by using drugs that specifically target GLUT1 expression in tumors (such as a histone deacetylase inhibitor SAHA), 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 SAHA transcriptionally downregulated LXR selectively in murine tumor cells in-vitro but not in normal corticotrophs. Based on these findings, we are now initiating a clinical trial of oral SAHA 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, my group 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. My group was also able to use this dataset to derive predictive rules that could help clinicians predict the durability of such hormonal remission. Successful pre-operative imaging of millimeter sized pituitary adenomas can lead to improved surgical outcomes in CD. My group is advancing imaging to help detect these adenomas. We developed a novel MRI coil that is designed to be used during surgery for CD6 and we are now starting a first-in-human trial of this coil. We also found that delayed post contrast MRI imaging was the most useful strategy to detect small, otherwise MRI invisible adenomas.