Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Abstract

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists-MIA-602, MIA-606, and MIA-690-on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.androgen-independent | G protein-coupled receptor | hypothalamic neurohormone | neuropeptide | targeted therapy

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

“…Although the presence of GHRH-R has been previously identified in multiple types of human cancers (11)(12)(13)(14)(15)(16)(17)(18)(19), the clinical importance of GHRH-R in the tumorigenic progression and patient outcome was unappreciated prior to this study. In this study, by analyzing multiple cohorts of GC patients of different races, we defined the heretofore undocumented associations between GHRH-R and poor survival of human GC.…”

“…( [11][12][13][14][15][16][17][18][19]. The GHRH/GHRH-R pathway is considered a growth factor-signaling pathway in these cancers and may modulate the activities of multiple intracellular pathways (11)(12)(13).…”

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

“…An autostimulatory loop, composed of tumor-derived GHRH and its tumoral receptors, can be disrupted by specific GHRH antagonists, resulting in inhibition of tumor growth in experimental models. GHRH antagonists induce marked reduction in the growth of prostate cancer cells in in vivo cancer xenograft models and in vitro (34).…”

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

“…7 GHRH and GHRH-R modulate cell proliferation and apoptosis in many tissues. [8][9][10][11][12][13][14][15][16] Antagonistic analogs of GHRH, synthesized in our laboratory, have been shown to inhibit the growth of various human cancers, 5 in part, by suppressing circulating GH/ IGF-1 levels. 17 Direct mechanisms involved in the dominant antitumor effects of GHRH antagonists appear to be based on blockage of the autocrine action of GHRH on tumors and on inhibition of the local production of IGF-I/II.…”