Improved Diagnosis and Treatment of Cushing's Disease

改进库欣病的诊断和治疗

• 批准号: 10265223
• 负责人: Prashant Chittiboina
• 金额: $ 172.48万
• 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/10265223
• 关键词: 6-Phosphofructo-2-kinase; Anterior Pituitary Gland; Benign; Blinded; CD6 antigen; Cell Cycle; Cell Survival; Clinical; Clinical Trials; Corticotropin; Corticotropin-Releasing Hormone; Data; Data Set; Detection; Diagnosis; Disease remission; Down-Regulation; Drug usage; 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; Image; In Vitro; Isoenzymes; Lead; Liver X Receptor; Longevity; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical; Metabolic; Morbidity - disease rate; Mus; Nuclear; Operative Surgical Procedures; Oral; POMC gene; 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; SLC2A1 gene; Serum; Stress Tests; Technology; Testing; Translating; Treatment Failure; United States National Institutes of Health; Vorinostat; adenoma; base; comparative; design; first-in-human; fluorodeoxyglucose positron emission tomography; glucose uptake; hexokinase; improved; improved outcome; inhibitor/antagonist; insight; lactate dehydrogenase A; metabolic imaging; millimeter; neoplastic cell; novel; overexpression; postoperative state; preservation; promoter; receptor; surgery outcome; treatment choice; tumor; tumorigenesis; uptake

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 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).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. We showed that corticotropinomas rely on glucose and the glycolytic pathway for survival.2 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.8 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.

我们发现，虽然促肾上腺皮质激素瘤是良性肿瘤，但它们与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同工酶转换HK-1到HK-2，乳酸脱氢酶A（LDH-A）到LDH-B和6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶-3（PFKFB 3）的核靶向介导的。我们还证实PFKFB 3的核靶向作用为人促肾上腺皮质激素瘤中细胞周期抑制剂p27的下调提供了一种因果机制。我们发现人促肾上腺皮质激素瘤过度表达葡萄糖转运蛋白1（GLUT 1），从而增加葡萄糖的摄取。然后，我们证明了GLUT 1的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。我们已经将这些发现转化为改善促肾上腺皮质激素瘤的FDG-PET检测（葡萄糖摄取的标志物）（NIH方案12-N-0007）。5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成像上是不可见的。通过CRH刺激，盲态神经放射科医生能够在PET成像上检测到40%的MRI不可见垂体腺瘤。 我们发现，促肾上腺皮质激素瘤依赖于葡萄糖和糖酵解途径的生存。2选择性抑制HK-2与3-溴丙酮酸导致显着降低糖酵解活性和细胞存活，特别是在人促肾上腺皮质激素瘤，而保留正常腺体。然后，我们发现，通过使用特异性靶向肿瘤中GLUT 1表达的药物（如组蛋白脱乙酰酶抑制剂SAHA），我们能够降低离体人促肾上腺皮质激素瘤的存活率和激素分泌。正常情况下，促肾上腺皮质激素的分泌是通过视黄酸受体（RXR）和肝X受体（LXR）的异源二聚体激活POMC基因来调节的。我们发现SAHA在体外小鼠肿瘤细胞中选择性下调LXR转录，但在正常促肾上腺皮质激素细胞中不下调。基于这些发现，我们现在开始在CD患者中进行口服SAHA的临床试验，以测试其在手术前使激素水平正常化的功效。 利用NIH独有的CD患者的大型临床数据集，我的小组 开发了一个关键的洞察力，即术后状态代表了内源性压力测试。这种见解现在允许临床医生仅从一个术后血清激素数据点预测CD手术后的激素缓解。8我的小组还能够使用该数据集来推导预测规则，这些规则可以帮助临床医生预测这种激素缓解的持久性。 毫米级垂体腺瘤的成功术前成像可改善CD的手术结局。我的团队正在推进成像技术来帮助检测这些腺瘤。我们开发了一种新的MRI线圈，设计用于CD 6的手术，我们现在正在开始对这种线圈进行首次人体试验。我们还发现，延迟后对比MRI成像是最有用的策略，以检测小，否则MRI不可见的腺瘤。