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 aimedat theARpathway resultinginandrogen- independentorhormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for themanagement of prostate cancer.We demonstrate that a relaxin hormone receptor antagonist, AT-001, an analog of humanH2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgenindependent 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. © 2014 Society for Endocrinology.