title: Relaxin receptor antagonist AT-001 synergizes with docetaxel in androgen-independent prostate xenografts.
abstract: Androgen hormones and the androgen receptor (AR) pathway are the main targets of anti-hormonal therapies for prostate cancer. However, resistance inevitably develops to treatments aimed at the AR pathway resulting in androgen-independent or hormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for the management of prostate cancer. We demonstrate that a relaxin hormone receptor antagonist, AT-001, an analog of human H2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgen-independent human prostate tumor xenografts. Chemically synthesized AT-001, administered subcutaneously, suppressed PC3 xenograft growth by up to 60%. AT-001 also synergized with docetaxel, standard first-line chemotherapy for HRPC, to suppress tumor growth by more than 98% in PC3 xenografts via a mechanism involving the downregulation of hypoxia-inducible factor 1 alpha and the hypoxia-induced response. Our data support developing AT-001 for clinical use as an anti-relaxin hormonal therapy for advanced prostate cancer.
authors.affiliation: Armour Therapeutics Inc., 124 Orchard View Boulevard, Toronto, Ontario, Canada Rna Diagnostics Inc., 595 Bay Street, Suite 1204, Toronto, Ontario, Canada Departments of Laboratory Medicine and Pathobiology Surgery, University of Toronto, Toronto, Ontario, Canada Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada Departments of Medicine Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada Division of Advanced Diagnostics - Infection and Immunity, Toronto General Research Institute (TGRI), University Health Network, Toronto, Ontario, Canada Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada Departments of Surgery and Medical Imaging, University of Toronto, Toronto, Ontario, Canada Division of Urology, Department of Surgical Oncology Prostate Centre, Princess Margaret Hospital Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Anton
authors.initials: A
authors.lastname: Neschadim
authors.forename: Laura B
authors.initials: LB
authors.lastname: Pritzker
authors.forename: Kenneth P H
authors.initials: KP
authors.lastname: Pritzker
authors.forename: Donald R
authors.initials: DR
authors.lastname: Branch
authors.forename: Alastair J S
authors.initials: AJ
authors.lastname: Summerlee
authors.forename: John
authors.initials: J
authors.lastname: Trachtenberg
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Silvertown
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D011944:Receptors, Androgen; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D043823:Taxoids; C033395:relaxin receptors; D000077143:Docetaxel
keywords: androgen independence; angiogenesis; anti-hormone therapy; docetaxel; prostate cancer; relaxin; relaxin antagonist; tumor xenografts