Improved Diagnosis and Treatment of Cushing's Disease

改进库欣病的诊断和治疗

• 批准号: 10018430
• 负责人: Prashant Chittiboina
• 金额: $ 91.02万
• 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/10018430
• 关键词: 6-Phosphofructo-2-kinase; Affect; Anterior Pituitary Gland; Benign; Blinded; CD6 antigen; Cell Cycle; Cell Survival; Cessation of life; Clinical; Clinical Trials; Corticotropin; Corticotropin-Releasing Hormone; Data; Data Set; Detection; Diagnosis; Disease; Disease remission; Down-Regulation; Drug usage; Endocrine; Epigenetic Process; Excision; Fructose-2,6-bisphosphatase; Gene Expression Profiling; Genetic; Genetic Transcription; Gland; Glucose; Goals; HDAC4 gene; Histone Deacetylase Inhibitor; Hormonal; Hormone secretion; Hormones; Human; Hydrocortisone; Hypertension; Image; Imaging technology; In Vitro; Isoenzymes; Lead; Life; Link; Liver X Receptor; Longevity; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Manuscripts; Mediating; Medical; Metabolic; Morbidity - disease rate; Morphology; Mus; Noise; Nuclear; Obesity; Operative Surgical Procedures; Oral; POMC gene; Panhypopituitarism; Pathway interactions; Patient-Focused Outcomes; Patients; Pituitary Corticotropin Secreting Adenoma; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Positron-Emission Tomography; Postoperative Period; Protocols documentation; Pyruvate; Radiation; Radiation therapy; SLC2A1 gene; Serum; Stress Tests; Testing; Translating; Treatment Failure; United States National Institutes of Health; Vorinostat; adenoma; base; comparative; contrast imaging; design; first-in-human; fluorodeoxyglucose positron emission tomography; glucose uptake; hexokinase; hypercortisolemia; improved; improved outcome; inhibitor/antagonist; insight; lactate dehydrogenase A; metabolic imaging; millimeter; neoplastic cell; novel; overexpression; postoperative state; preservation; promoter; receptor; success; surgery outcome; treatment choice; tumor; tumorigenesis; uptake

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.

经蝶手术 (TSS) 是治疗导致库欣病 (CD) 的促肾上腺皮质激素腺瘤的最佳治疗方法。尽管 CD 是由良性垂体肿瘤引起的，但它会极大地影响患者的生活。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、形态变化和死亡。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会接受多种治疗，包括放疗和终身皮质醇抑制治疗。 TSS 的成功与术前准确检测垂体肿瘤的能力直接相关。常规垂体磁共振成像 (MRI) 在高达 50% 的 CD 病例中无法检测 CA 肿瘤，可能是由于肿瘤尺寸小或 MRI 与噪声对比度较差。当术前通过 MRI 识别肿瘤时，治愈率可达 90%。当手术前未通过影像学检查发现腺瘤时，探查手术治愈患者的成功率要低得多，并且在许多情况下，最终会导致放射治疗和全垂体功能减退症。 我们发现，尽管促肾上腺皮质激素瘤是良性肿瘤，但它们会像恶性肿瘤一样经历代谢重编程。我们发现代谢重编程是通过己糖激酶-1 (HK-1)​​ 至 HK-2、乳酸脱氢酶 A (LDH-A) 至 LDH-B 的同工酶转换以及 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-3 (PFKFB3) 的核靶向介导的。 13 我们还假设 PFKFB3 的核靶向提供了 人促肾上腺皮质激素瘤中细胞周期抑制剂 p27 下调的因果机制。我们发现人类促肾上腺皮质激素瘤过度表达葡萄糖转运蛋白 1 (GLUT1)，从而增加葡萄糖的摄取。然后我们证明 GLUT1 表达可以通过促肾上腺皮质激素释放激素 (CRH) 等促分泌素的刺激进行转录调节。我们已将这些发现转化为改进促肾上腺皮质激素瘤的 FDG-PET 检测（葡萄糖摄取标记）（NIH 方案 12-N-0007）。我们发现 CRH 刺激导致腺瘤中平均 FDG 摄取增加。通常，这些肿瘤在 MRI 成像中是不可见的。通过 CRH 刺激，盲法神经放射科医生能够通过 PET 成像检测出 40% 的 MRI 不可见垂体腺瘤（已提交手稿）。 我们发现促肾上腺皮质激素瘤依赖葡萄糖和糖酵解途径生存。用 3-溴丙酮酸选择性抑制 HK-2 会显着降低糖酵解活性和细胞存活率，特别是在人类促肾上腺皮质激素瘤中，同时不影响正常腺体。然后我们发现，通过使用专门针对肿瘤中 GLUT1 表达的药物（例如组蛋白脱乙酰酶抑制剂 SAHA），我们能够降低人促肾上腺皮质激素瘤的体外存活率和激素分泌。通常，ACTH 的分泌是通过视黄酸受体 (RXR) 和肝脏 X 受体 (LXR) 的异二聚体激活 POMC 基因的启动子来调节的。我们发现 SAHA 在体外小鼠肿瘤细胞中选择性地转录下调 LXR，但在正常促肾上腺皮质激素细胞中则不然。基于这些发现，我们现在正在 CD 患者中启动口服 SAHA 的临床试验，以测试其在术前恢复激素水平正常化方面的功效。 利用 NIH 独有的 CD 患者的大型临床数据集，我的团队得出了一个重要的见解，即术后状态代表了内源性压力测试。现在，这一见解使临床医生能够仅根据一个术后血清激素数据点来预测 CD 手术后的激素缓解情况。我的团队还能够使用该数据集得出预测规则，帮助临床医生预测这种激素缓解的持久性。 对毫米大小的垂体腺瘤进行成功的术前成像可以改善 CD 的手术结果。我的团队正在推进成像技术以帮助检测这些腺瘤。我们开发了一种新型 MRI 线圈，设计用于 CD6 手术期间使用，现在我们正在开始对该线圈进行首次人体试验。我们还发现，延迟对比后 MRI 成像是检测小型 MRI 不可见腺瘤的最有用策略。