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Schally Lab

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Investigator / Contact Person Andrew Schally

Research

Hypothalamic growth hormone-releasing hormone (GHRH), besides controlling the release of GH from the pituitary, also acts on and is present in various extra-pituitary tissues. Consequently analogs of GHRH are likely to find various therapeutic applications. For this purpose we synthesize by sold phase methods diverse series of agonists and antagonists of GHRH, using the biologically active sequence of GHRH (1-29)NH2. In the Miami class of GHRH antagonists, based on the favorable physiological properties of fluorinated peptides, we incorporated pentafluoro-Phe at positions 6 or 10 and Orn at positions 12 and 21 into the structures of several of our analogs of GHRH that previously proved to have anticancer activities. In addition, w-amino acids were incorporated either at the N- or at the C- terminus of these GHRH antagonists, with the aim of improving bioavailability, reducing excretion and biodegradation, and increasing the affinity to GHRH receptors.

Among these new GHRH antagonists developed for treatment of various cancers are MIA-602, MIA-609, MIA-690 and others. Extensive preclinical evaluation of these new GHRH antagonists, especially MIA-602 and MIA-690 has been carried out in athymic nude mice bearing xenografts of a wide variety of human cancer lines. The efficacy of the various GHRH analogs has been demonstrated in models of castration resistant prostate cancer, pancreatic, colorectal, gastric, renal, and bladder cancer, brain tumors, such as glioblastomas, lung cancer (SCLC and non-SCLC), melanoma and hepatoma. Antitumor effects of GHRH analogs have also been demonstrated by us in vivo in nude mice bearing human breast cancer, including the triple negative variety and ovarian and endometrial cancer lines, and in acute myeloid leukemia and papillary thyroid cancer. The pathophysiologic basis underlying the response to GHRH antagonist is explained by the presence of GHRH and GHRH receptors (GHRH-R) in a variety of tumors. We also demonstrated that combinations of GHRH analogs with doxorubicin or taxol inhibit tumor growth better than single drugs. New AVR class of more potent GHRH antagonists will be evaluated in various cancer models.

In collaboration with Professor Hao Zhang at Shantou University Medical College, China, using survival analyses of multipole cohorts of gastric cancer patients in China, totaling 957 patients, we demonstrated that increase GHRH-R level in tumor specimens correlated with poor survival and is an independent predictor of patient prognosis. We have elucidated several mechanisms to explain the antitumor action of GHRH antagonists. Tumor inhibition produced by these GHRH antagonists is associated with suppression in the expression of VEGF, bFGF, pAKT, and EGF/Her receptor family and interference in PKC and MAPK signaling. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1(PAK1)-mediated signal transducer and activator of transcription 3(STAT3)/nuclear factor-?B inflammatory pathway. We have also demonstrated inhibitory effects of new GHRH antagonists, in benign prostatic hyperplasia (BPH) using BPH human cell line in vitro and in vivo. GHRH antagonists could be also used for the treatment of acute ocular inflammation. We also demonstrated that GHRH antagonists induce apoptosis in retinoblastoma cells and thus could be developed for therapy of this tumor. We have shown that antagonists of GHRH influence neural activity and function. We then documented in a transgenic mouse model of Alzheimer’s disease, that antagonist MIA-690 improves cognitive performance (latency, cumulative index), and decreases ROS formation in vitro. GHRH antagonists also inhibit the accumulations of ?-amyloid rafts and ? filament concentrations. The effects of MIA-690 in the Alzheimer’s model must be extended to evaluate possible application of GHRH analogs for therapy of Alzheimer’s disease.