title: 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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Cale D
authors.initials: CD
authors.lastname: Fahrenholtz
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.forename: Maria I
authors.initials: MI
authors.lastname: Garcia
authors.forename: Marta
authors.initials: M
authors.lastname: Zarandi
authors.forename: Ren-Zhi
authors.initials: RZ
authors.lastname: Cai
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Burnstein
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013997:Time Factors
chemical_list: D000728:Androgens; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D013007:Growth Hormone-Releasing Hormone; D017430:Prostate-Specific Antigen
keywords: G protein-coupled receptor; androgen-independent; hypothalamic neurohormone; neuropeptide; targeted therapy