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Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ - Sci Rep (2015)

Bottom Line: Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR.In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice.In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs.

View Article: PubMed Central - PubMed

Affiliation: Orion Corporation, Orion Pharma, Finland.

ABSTRACT
Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

No MeSH data available.


Related in: MedlinePlus

The inhibition of the nuclear translocation of AR.A. Representative confocal microscopic images of HS-HEK293 cells treated with DMSO (A), testosterone (B), testosterone combined with bicalutamide (C), or testosterone combined with ODM-201 (D). The concentrations of testosterone and test compounds were 0.3 nM and 1.0 μM, respectively. The images are cropped from photographs taken at magnification x63. B. AR overexpressing HS-HEK293 cells were treated with 0.3 μM of ODM-201, ORM-15341, bicalutamide, enzalutamide, or ARN-509 with 0.3 nM testosterone in steroid-depleted medium for 4 hours, immunolabeled with an AR antibody conjugated with Alexa Fluor® 488, and imaged with Cellomics ArrayScan VTI HCS reader. Bars represent AR nuclear localization as percentage of the control (testosterone). All data points are means of triplicates +SEM. Test = testosterone.
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f3: The inhibition of the nuclear translocation of AR.A. Representative confocal microscopic images of HS-HEK293 cells treated with DMSO (A), testosterone (B), testosterone combined with bicalutamide (C), or testosterone combined with ODM-201 (D). The concentrations of testosterone and test compounds were 0.3 nM and 1.0 μM, respectively. The images are cropped from photographs taken at magnification x63. B. AR overexpressing HS-HEK293 cells were treated with 0.3 μM of ODM-201, ORM-15341, bicalutamide, enzalutamide, or ARN-509 with 0.3 nM testosterone in steroid-depleted medium for 4 hours, immunolabeled with an AR antibody conjugated with Alexa Fluor® 488, and imaged with Cellomics ArrayScan VTI HCS reader. Bars represent AR nuclear localization as percentage of the control (testosterone). All data points are means of triplicates +SEM. Test = testosterone.

Mentions: To investigate the effect of antiandrogens on the subcellular localization of AR, immunocytochemical labeling with an anti-AR antibody in AR overexpressing HS-HEK293 cells was used. As shown in Fig. 3A, AR was predominantly cytoplasmic in the absence of androgen, and exposure to testosterone markedly increased the nuclear-cytoplasmic ratio of AR immunofluorescence intensity, indicating the movement of AR from the cytoplasm to the nucleus. In the presence of bicalutamide, AR was largely nuclear, indicating that bicalutamide failed to block the testosterone-induced nuclear translocation of AR. In contrast, in the presence of ODM-201, ORM-15341, enzalutamide, or ARN-509, AR was predominantly cytoplasmic, showing that these antiandrogens inhibit the androgen-induced nuclear translocation of overexpressed AR to same extent (Fig. 3A,B). Corresponding results were obtained also with an AR-overexpressing PC cell line (LNCaP) (Supplementary Fig. S2).


Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ - Sci Rep (2015)

The inhibition of the nuclear translocation of AR.A. Representative confocal microscopic images of HS-HEK293 cells treated with DMSO (A), testosterone (B), testosterone combined with bicalutamide (C), or testosterone combined with ODM-201 (D). The concentrations of testosterone and test compounds were 0.3 nM and 1.0 μM, respectively. The images are cropped from photographs taken at magnification x63. B. AR overexpressing HS-HEK293 cells were treated with 0.3 μM of ODM-201, ORM-15341, bicalutamide, enzalutamide, or ARN-509 with 0.3 nM testosterone in steroid-depleted medium for 4 hours, immunolabeled with an AR antibody conjugated with Alexa Fluor® 488, and imaged with Cellomics ArrayScan VTI HCS reader. Bars represent AR nuclear localization as percentage of the control (testosterone). All data points are means of triplicates +SEM. Test = testosterone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490394&req=5

f3: The inhibition of the nuclear translocation of AR.A. Representative confocal microscopic images of HS-HEK293 cells treated with DMSO (A), testosterone (B), testosterone combined with bicalutamide (C), or testosterone combined with ODM-201 (D). The concentrations of testosterone and test compounds were 0.3 nM and 1.0 μM, respectively. The images are cropped from photographs taken at magnification x63. B. AR overexpressing HS-HEK293 cells were treated with 0.3 μM of ODM-201, ORM-15341, bicalutamide, enzalutamide, or ARN-509 with 0.3 nM testosterone in steroid-depleted medium for 4 hours, immunolabeled with an AR antibody conjugated with Alexa Fluor® 488, and imaged with Cellomics ArrayScan VTI HCS reader. Bars represent AR nuclear localization as percentage of the control (testosterone). All data points are means of triplicates +SEM. Test = testosterone.
Mentions: To investigate the effect of antiandrogens on the subcellular localization of AR, immunocytochemical labeling with an anti-AR antibody in AR overexpressing HS-HEK293 cells was used. As shown in Fig. 3A, AR was predominantly cytoplasmic in the absence of androgen, and exposure to testosterone markedly increased the nuclear-cytoplasmic ratio of AR immunofluorescence intensity, indicating the movement of AR from the cytoplasm to the nucleus. In the presence of bicalutamide, AR was largely nuclear, indicating that bicalutamide failed to block the testosterone-induced nuclear translocation of AR. In contrast, in the presence of ODM-201, ORM-15341, enzalutamide, or ARN-509, AR was predominantly cytoplasmic, showing that these antiandrogens inhibit the androgen-induced nuclear translocation of overexpressed AR to same extent (Fig. 3A,B). Corresponding results were obtained also with an AR-overexpressing PC cell line (LNCaP) (Supplementary Fig. S2).

Bottom Line: Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR.In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice.In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs.

View Article: PubMed Central - PubMed

Affiliation: Orion Corporation, Orion Pharma, Finland.

ABSTRACT
Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

No MeSH data available.


Related in: MedlinePlus