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.
Preclinical evaluation of analogs of growth hormone-releasing hormone (GHRH), will continue in oncological and non-oncological animal models. Newly synthesized GHRH antagonists of AVR class will be tested in nude mice bearing human castration resistant prostatic cancer (CRPC), lung cancer (SCLC and N-SCLC), gastric, pancreatic, breast, ovarian, endometrial, colorectal and brain cancer lines. In view of recent demonstration of inhibitory effects of GHRH agonists on tumor growth in vivo by downregulation of GHRH receptors, GHRH agonists, such as MR-409 activity will be tested in prostate cancer and selected tumors. GHRH antagonists will be also evaluated for various non-oncological applications in models of dyslipidemia, lung fibrosis and sarcoidosis. Both GHRH agonists and antagonists will be explored in models of Alzheimer?s disease, post- traumatic stress disorder (PTSD), traumatic brain injury (TBI), and Gulf War illness (GWI). GHRH agonists will be investigated for applications in cardiology, treatment of diabetes and eye diseases.
