The Dual Androgen Receptor and Glucocorticoid Receptor Antagonist CB-03-10 as Potential Treatment for Tumors that have Acquired GR-mediated Resistance to AR Blockade

Abstract

CB-03-10 (cortexolone 17a-valerate-21-propionate) is a synthetic steroidal compound derived from cortexolone (11-deoxycortisone), an intermediate in cortisol biosynthesis. Characterization of the activity of CB-03-10 and its main related compound CB-03-05 (cortexolone 17a-valerate) included in vitro binding to the androgen and glucocorticoid receptors (AR and GR), antagonism of AR and GR transcriptional activities, and screening for antitumor activity across a selected panel of human prostate and in triplenegative breast cancer cell lines. CB-03-10 cytotoxic activity in these cancer cell lines was in the low micromolar range and was primarily associated with induction of the apoptotic cascade via activation of caspases. The compound's potential for antitumor activity was verified in a murine xenograft model utilizing the AR-positive LNCaP prostate cancer cell line as well as in an orthotopic model utilizing AR-negative/GR-positive MDA-MB-231 breast cancer cell line. Orally administered CB-03-10 inhibited prostate tumor growth and orthotopically implanted breast tumor growth in these mice and maintained body weight, as compared with vehicle-treated mice. On the basis of AR/GR binding affinities, antagonism of androgen and glucocorticoid-dependent transcriptional activities, and AR/GR mRNA and protein expression, the mechanism of tumor growth suppression is related to AR and GR antagonist activities. Importantly, these compounds lack biologically relevant AR/GR agonist activities. Overall, these preclinical findings support the selection of CB-03-10 for further development as an anticancer agent in cases where resistance to AR-targeted therapy or chemotherapy, via upregulation of GR activity, continues to limit the efficacy and duration of clinical benefit with these interventions.

The Potential of Hormonal Therapies for Treatment of Triple-Negative Breast Cancer

“…Additionally, insight into the interactions between these hormone receptors is needed. While a small number of studies have reported on the crosstalk between the various hormone receptors [97][98][99][100], their mechanism of action is still largely unknown. Thus, further research regarding these hormonal receptors in TNBC could lead to a new effective treatment for some patients.…”

From Therapy Resistance to Targeted Therapies in Prostate Cancer

“…Gefitinib ( 89 ), BEZ235 ( 110 ), RAD001 ( 124 ) or RU486 ( 131 ) were also reported to re-sensitize resistant cells to standard chemotherapy agents ( Supplementary Table 1 ). Interestingly, CUDC-907 ( 101 ), CB-03-10 ( 130 ) and MP470 ( 135 ), in addition to selective RTK inhibition, were found to inhibit HDAC6, AR and EGFR, respectively. These drugs caused cytotoxic effects in resistant cells ( Supplementary Table 1 ), indicating a possible benefit of targeting multiple pathways for management of resistant PCa.…”

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

“…Besides drug combination, a multiple target drug (a single drug acting on multiple targets) strategy has provided a promising opportunity for drug discovery and development. , Dervan’s group reported a pyrrole–imidazole polyamide ARE-1 showing both AR and GR transcription blockage and inhibition of ENZa-resistant mCRPC xenografts’ progression . In 2020, Rosette et al discovered a dual AR/GR antagonist, CB-03-10 , and its metabolite CB-03-05 , which inhibited the transcriptional activities of AR and GR in a dose-dependent manner (Figure ). Jorda et al found that a series of hydrocortisone ester compounds could repressively target AR and GR in PCa in vitro .…”