Improved Diagnosis and Treatment of Cushing's Disease

改进库欣病的诊断和治疗

• 批准号: 9157582
• 负责人: Prashant Chittiboina
• 金额: $ 50.74万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9157582
• 关键词: Adrenal Glands; Affect; Anilides; Anterior Pituitary Gland; Benign; Biochemical; Biological; Breast Microcalcification; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Corticotropin; Deoxyglucose; Detection; Diagnosis; Disease; Disease remission; Dose; Effectiveness; Endocrine; Excision; FDA approved; Fluorine; Glucose Transporter; Goals; Histones; Hormonal; Hydrocortisone; Hydroxamic Acids; Hypertension; Image; Image Analysis; Imagery; Imaging technology; Institutional Review Boards; Investigation; Laboratories; Lead; Lesion; Life; Link; Longevity; Magnetic Resonance Imaging; Medical; Metabolic; Morbidity - disease rate; Noise; Obesity; Operative Surgical Procedures; Outcome; Output; Panhypopituitarism; Patients; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Positron-Emission Tomography; Production; Property; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Reporting; Signal Transduction; Sinus; Study Subject; Surface; Testing; Time; Treatment Failure; Up-Regulation; Use Effectiveness; adenoma; base; capsule; design; glucose uptake; improved; inhibitor/antagonist; neoplastic cell; novel; novel therapeutics; pars intermedia; pre-clinical; success; tool; tumor; ultra high resolution

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. Improved MRI Imaging of the Pituitary Gland: We have developed a novel intracavitary MRI surface coil (the endosphenoidal coil or ESC) that is designed to be used during TSS. In pre-clinical cadaveric testing, we have demonstrated 10-20 fold increase in signal-to-noise ratio (SNR) when using the ESC compared to standard clinical imaging. High SNR allowed us to perform ultra high-resolution imaging of cadaveric pituitary gland to reveal features not normally visible on clinical imaging, including the pituitary capsule, the intercavernous sinus and microcalcifications in the pars intermedia. Based on the findings from the cadaveric study, we have designed a Phase 0 clinical trial to evaluate the feasibility of using ESC during TSS. The study is being submitted to the CNS IRB and FDA for approval. The study will be a non-randomized, pilot study of subjects requiring TSS for pituitary lesions. The study will evaluate the feasibility and effectiveness of using ESC as a clinical tool for imaging evaluation of pituitary tumors during TSS. Metabolic Imaging of the Pituitary Gland: Other strategies to detect pituitary adenomas can be developed that exploit the physiologic properties of these lesions. Specifically, fluorine-2-18-deoxyglucose (FDG) positron emission tomography (PET) imaging may help identify biologically active pituitary adenomas. Previous PET studies using FDG have reported locating tumors that were not visible with MRI, hinting at a potential use in detecting MR negative pituitary adenomas. In an ongoing laboratory effort, we have discovered that secretagogue stimulation can modulate their glucose uptake in a delayed fashion that is dependent on membranous translocation and transcriptional upregulation of glucose transporter 1 (GLUT1). Based on these findings, we have amended and continued an ongoing clinical trial to evaluate the effect of secretagogue stimulation on FDG-PET visualization of pituitary adenomas in CD. New therapeutic options for CD In instances where TSS fails to cure CD patients, tumor cells are targeted by adjunctive therapies including radiation. Radiation is successful in 50% of patients, but it may take up to 2 3 years to achieve biochemical remission. During this time, hormonal suppression of the adrenal glands in necessary. Our recent laboratory investigations have shown that histone deacytelase (HDAC) inhibition with suberolyl anilide hydroxamic acid (SAHA) may achieve three goals that may lead to improved management of CD patients that have failed TSS. We have seen that SAHA leads to a reduction in ACTH output from corticotroph cells, and also causes a dose dependent reduction in tumor cell viability. It is also well known that HDAC inhibitors are potent radiation sensitizers. We are developing a clinical trial to investigate the effectiveness of SAHA (an FDA approved drug) in CD patients. We believe that SAHA will lead to improved management of CD as it may reduce the ACTH production in remnant tumors, cause tumor size reduction and sensitize the tumors to radiation therapy.

经蝶窦手术（TSS）是治疗导致库欣病（CD）的促皮质激素腺瘤的最佳方法。虽然由良性垂体肿瘤引起，但乳糜泻可以严重影响患者的生活。促肾上腺皮质激素（ACTH）升高和由此产生的高皮质醇血症可导致肥胖、高血压、高凝血性、形态改变和死亡。成功的TSS可以在保留70 - 80%患者内分泌功能的同时，立即治愈乳糜泻。没有通过TSS获得缓解的患者最终需要接受多种治疗，包括放疗和终身皮质醇抑制治疗。