Development of new therapies for cancer and other diseases and conditions using analogs of growth hormone-releasing hormones (GHRH)

使用生长激素释放激素 (GHRH) 类似物开发癌症和其他疾病和病症的新疗法

• 批准号: 10013922
• 负责人: Andrew Schally
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013922
• 关键词: Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Animals; Antiinflammatory Effect; Area; Beta Cell; Bladder; Brain; Breast; Cardiac; Cardiac Myocytes; Cardiology; Castration; Cell Proliferation; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Code; Collaborations; Colorectal; Colorectal Cancer; Deterioration; Development; Diabetes Mellitus; Disease; Down-Regulation; Dyslipidemias; Endometrial Carcinoma; Engraftment; Evaluation; Eye diseases; Family suidae; Female; Fibrosis; Goals; Growth; Gulf War; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hormone Antagonists; Human; In Vitro; Incidence; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; International Health Problems; Investigation; Islet Cell; Islets of Langerhans; Lead; Left Ventricular Dysfunction; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Medicine; Modeling; Mus; Myocardial Infarction; Myocardium; Natural regeneration; Non-Small-Cell Lung Carcinoma; Nude Mice; Ophthalmology; Output; Pancreas; Pancreatic carcinoma; Patients; Peripheral Vascular Diseases; Phase; Population; Post-Traumatic Stress Disorders; Production; Prostate; Prostate carcinoma; Pulmonary Fibrosis; Pulmonary Sarcoidosis; Rattus; Research; Research Personnel; Resistance; Sarcoidosis; Somatotropin-Releasing Hormone; Stomach; Structure; Structure of beta Cell of islet; Testing; Therapeutic; Thyroid Gland; Transgenic Mice; Transplantation; Traumatic Brain Injury; Uveitis; Veterans; Work; Xenograft procedure; age group; analog; antitumor effect; attenuation; base; cancer therapy; castration resistant prostate cancer; clinical application; cognitive performance; coronary fibrosis; experimental study; global health; growth hormone-releasing hormone receptor; hormone analog; improved; in vivo; islet; leukemia; male; malignant breast neoplasm; malignant stomach neoplasm; men; mortality; myocardial damage; novel strategies; novel therapeutics; patient population; pre-clinical; preclinical evaluation; preclinical study; prevent; programs; repaired; side effect; tissue repair; treatment effect; tumor; tumor growth; wound; wound healing

In view of documented activities and potential extensive applications of the antagonistic and agonistic analogs of growth hormone-releasing hormone (GHRH) in various areas of medicine, including the treatment of cancer, infarcted heart, diabetes, wounds and eye diseases, these projects will continue. Our main goal will be further development of analogs of GHRH, which appear to be free of side effects. Newly synthesized antagonists of growth hormone-releasing hormone (GHRH) of AVR class with high antitumor activities will be evaluated for their inhibitory effects on growth of various malignancies, including castration resistant prostate carcinoma (CRPC), small cell and non-small cell lung carcinoma (SCLC and non-SCLC), pancreatic carcinoma, colorectal and gastric cancers, breast, ovarian and endometrial cancers, malignant brain tumors, as well as leukemia. All these cancers express receptors for GHRH to which the anti-tumor GHRH analogs are targeted. The oncological evaluations will be carried out in various human cancer lines xenografted into athymic mice and in vitro. The cancers selected represent major national and international health problems that all affect US veterans and are responsible for a large number of deaths. About 30,000 men with CRPC, die yearly in the USA. We will evaluate experimentally, new approaches for treatment of CRPC, based on new potent AVR class GHRH antagonists. The incidence of these cancers and the mortality rates in VA patients generally reflect similar rates for the US population of corresponding age groups. Therefore, the results of the proposed research will be of benefit to both the male and female VA patient population. Alzheimer’s disease is a serious global health problem. GHRH antagonists of Miami class, such as MIA-690 show beneficial effects in transgenic mouse models of Alzheimer’s disease (AD) and evaluation of the effects of new AVR class GHRH antagonists will continue in collaboration with several VA and non-VA groups. GHRH antagonists of MIA Class and AVR Class will be also tested in models of eye diseases, dyslipidemia, and lung diseases, like fibrosis and sarcoidosis. The investigator will also continue his work on agonists of GHRH of MR Class, such as MR-409, which have been previously synthesized. This work will include the evaluation in some cancers, especially CRPC of recently discovered anti-tumor effects of GHRH agonists mediated by downregulation of GHRH receptors. However, the main evaluations of GHRH agonists will be done in experimental studies in animals for uses in cardiology, treatment of diabetes, wound healing and eye diseases, such as uveitis. Both the agonists and antagonists of GHRH exert antioxidative anti- inflammatory effects. These preclinical studies will be carried out with several groups of expert collaborators. Agonists of GHRH act on cells with receptors for GHRH and in cardiology improve cardiac structure and function. Thus, in collaboration, agonists of GHRH of MR class, such as MR-409, will be subjected to cardiological investigations to determine their therapeutic potential in treatment of heart failure and/or left ventricular (LV) dysfunction, cardiac fibrosis and cardiac hypertrophy. Agonists of MR class will also continue to be evaluated in models of diabetes type I and II since they increase the proliferation of pancreatic islet cells after transplantation and augment insulin output of pancreatic islet cells. Wound healing affects millions of people, particularly veterans, and is improved by GHRH agonists. The overall program is aimed at improving the treatment for various cancers and other diseases and conditions by the use of GHRH analogs and to provide preclinical basis for clinical trials. The findings obtained will be important clinically and should lead to improvements in therapies. The preclinical information acquired will be used to start phase I, II and III clinical trials and apply for IND.

鉴于记录在案的拮抗和激动型类似物的活性和潜在的广泛应用 生长激素释放激素(GHRH)在包括癌症治疗在内的各个医学领域的应用， 对于心脏病、糖尿病、创伤和眼疾，这些项目将继续下去。我们的主要目标将是进一步 开发GHRH类似物，似乎没有副作用。新合成的阿司匹林拮抗剂 将对具有高抗肿瘤活性的AVR类生长激素释放激素(GHRH)进行评估 抑制各种恶性肿瘤的生长，包括耐去势前列腺癌(CRPC)， 小细胞和非小细胞肺癌(SCLC和非小细胞肺癌)、胰腺癌、结直肠癌和 胃癌、乳腺癌、卵巢癌和子宫内膜癌、恶性脑瘤以及白血病。所有这些都是 肿瘤表达GHRH受体，抗肿瘤的GHRH类似物针对该受体。肿瘤学 将在不同的人类癌细胞系中进行评估，移植到裸鼠和体外。这个 选定的癌症代表了影响美国退伍军人的重大国家和国际健康问题，并 造成了大量的死亡。在美国，每年约有3万名患有慢性前列腺癌的男性死亡。我们将评估 实验上，基于新的有效的AVR类GHRH拮抗剂，为CRPC的治疗提供了新的方法。 这些癌症的发病率和退伍军人管理局患者的死亡率通常反映了美国类似的比率 相应年龄段的人口。因此，拟议的研究结果将有益于 男性和女性VA患者群体。阿尔茨海默病是一个严重的全球健康问题。GHRH 迈阿密类拮抗剂，如MIA-690，在阿尔茨海默病转基因小鼠模型中显示出有益的效果 疾病(AD)和评估新的AVR类GHRH拮抗剂的效果将继续合作 有几个VA组和非VA组。MIA级和AVR级的GHRH拮抗剂也将在 眼部疾病、血脂异常和肺部疾病的模型，如纤维化和结节病。调查员还将 继续他对MR类GHRH激动剂的工作，如先前合成的MR-409。 这项工作将包括对一些癌症，特别是CRPC新近发现的抗肿瘤作用的评估 通过下调GHRH受体介导的GHRH激动剂。然而，GHRH的主要评价 激动剂将在动物的实验研究中用于心脏病、糖尿病、创伤的治疗 治疗和眼部疾病，如葡萄膜炎。GHRH的激动剂和拮抗剂均具有抗氧化作用。 发炎效应。这些临床前研究将与几组专家合作者一起进行。 GHRH激动剂通过GHRH受体作用于细胞，在心脏病学中改善心脏结构和功能。 因此，在合作中，MR类GHRH激动剂，如MR-409，将受到心脏病学的影响 研究确定它们在治疗心力衰竭和/或左心室(LV)方面的治疗潜力 心脏功能障碍、心肌纤维化和心肌肥厚。MR类激动剂也将继续在 I型和II型糖尿病模型的建立及其对移植后胰岛细胞增殖的影响 增加胰岛细胞的胰岛素输出。伤口愈合影响着数百万人，尤其是 退伍军人，并通过GHRH激动剂改善。整个计划旨在改善对儿童的治疗 通过使用GHRH类似物和为各种癌症和其他疾病的病情提供临床前依据 用于临床试验。所获得的发现将在临床上具有重要意义，并应导致治疗方法的改进。 获得的临床前信息将用于启动I、II和III期临床试验并申请IND。