Improved Diagnosis and Treatment of Cushing's Disease

改进库欣病的诊断和治疗

• 批准号: 9358615
• 负责人: Prashant Chittiboina
• 金额: $ 98.82万
• 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/9358615
• 关键词: Adrenal Glands; Affect; 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; 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; 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; SLC2A1 gene; Signal Transduction; Sinus; Study Subject; Surface; Testing; Time; Treatment Failure; Up-Regulation; Use Effectiveness; adenoma; base; capsule; design; glucose uptake; improved; improved outcome; inhibitor/antagonist; neoplastic cell; novel; novel therapeutics; pars intermedia; pre-clinical; success; tool; treatment choice; 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.

经蝶窦手术是治疗引起库欣病的促肾上腺皮质激素腺瘤的最佳方法。虽然是由良性垂体瘤引起的，但CD会严重影响患者的生活。促肾上腺皮质激素（ACTH）增加和由此产生的高皮质醇血症可导致肥胖、高血压、高凝状态、形态学改变和死亡。成功的TSS可以立即治愈CD，同时保留约70 - 80%患者的内分泌功能。TSS未达到缓解的患者最终接受许多治疗，包括放射治疗和终身皮质醇抑制治疗。 TSS的成功与术前准确检测垂体瘤的能力直接相关。在高达50%的CD病例中，常规垂体磁共振成像（MRI）未能检测到CA肿瘤，可能是由于体积小或MRI对噪声的对比度差。 当肿瘤在手术前在MRI上被识别时，治愈率可以达到90%。当腺瘤在手术前的成像上没有被识别时，探查性手术在治愈患者方面的成功率要低得多，并且在许多情况下，最终导致放射治疗和全垂体功能减退。 改进的松果体MRI成像： 我们开发了一种新型的腔内MRI表面线圈（蝶窦内线圈或ESC），设计用于TSS。在临床前尸体测试中，我们已经证明与标准临床成像相比，使用ESC时信噪比（SNR）增加了10-20倍。高SNR使我们能够对尸体垂体进行超高分辨率成像，以显示临床成像中通常不可见的特征，包括垂体囊、海绵间窦和中间部的微钙化。 根据尸体研究的结果，我们设计了一项0期临床试验，以评估在TSS期间使用ESC的可行性。该研究正在提交给CNS IRB和FDA批准。本研究将是一项在需要TSS治疗垂体病变的受试者中进行的非随机、初探性研究。本研究将评估使用ESC作为TSS期间垂体瘤影像学评估的临床工具的可行性和有效性。 前列腺的代谢成像： 其他策略来检测垂体腺瘤可以开发利用这些病变的生理特性。 具体来说，氟-2-18-脱氧葡萄糖（FDG）正电子发射断层扫描（PET）成像可能有助于识别生物活性垂体腺瘤。先前使用FDG的PET研究报告了MRI无法发现的肿瘤定位，暗示了在检测MR阴性垂体腺瘤中的潜在用途。 在一项正在进行的实验室研究中，我们发现促分泌素刺激可以以延迟的方式调节其葡萄糖摄取，这种方式依赖于葡萄糖转运蛋白1（GLUT 1）的膜转位和转录上调。基于这些发现，我们修改并继续进行一项正在进行的临床试验，以评估促分泌素刺激对CD垂体腺瘤FDG-PET显像的影响。 CD的新治疗选择 在TSS未能治愈CD患者的情况下，肿瘤细胞被包括放射的连续疗法靶向。放射治疗是成功的，在50%的患者，但它可能需要长达2 - 3年，以实现生化缓解。在此期间，肾上腺的激素抑制是必要的。 我们最近的实验室研究表明，用辛二酰苯胺异羟肟酸（SAHA）抑制组蛋白脱乙酰酶（HDAC）可以实现三个目标，这可能导致TSS失败的CD患者的管理得到改善。我们已经看到，SAHA导致促肾上腺皮质激素细胞的ACTH输出减少，并且还导致肿瘤细胞活力的剂量依赖性降低。众所周知，HDAC抑制剂是强效的辐射增敏剂。 我们正在开发一项临床试验，以调查SAHA（FDA批准的药物）在CD患者中的有效性。我们相信，SAHA将导致改善CD的管理，因为它可以减少残留肿瘤中ACTH的产生，导致肿瘤体积缩小，并使肿瘤对放射治疗敏感。