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: 10454832
• 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/10454832
• 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; Female; Fibrosis; Goals; Growth; 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; Non-Small-Cell Lung Carcinoma; Nude Mice; Ophthalmology; Output; Pancreas; Pancreatic carcinoma; Patients; Peripheral Vascular Diseases; Persian Gulf Syndrome; Persons; 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; antagonist; 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; porcine model; pre-clinical; preclinical evaluation; preclinical study; prevent; programs; regeneration potential; 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.

鉴于文献记载的拮抗和激动类似物的活性和潜在的广泛应用