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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

Growth inhibition of VCaP cells in in vitro and in vivo CRPC settings.A. VCaP prostate cancer cells were treated with a submaximal concentration of mibolerone (0.1 nM) and different concentrations of test compounds in steroid-depleted medium, and cell growth was measured after 4 days of incubation using a WST-1 cell proliferation assay. The representative graph of the inhibitory effects of test compounds on the viability of VCaP cells is shown. All data points are means of quadruplicates ±SEM. IC50 values are presented in parentheses. B. Mean tumor volumes (mm3, +SEM) in castrated (ORX) nude mice with subcutaneous VCaP tumors after the oral treatment with ODM-201 (50 mg/kg, once or twice daily) or enzalutamide (20 mg/kg, once daily) for 37 days (n = 6−11). SHAM, sham-operated. ***p < 0.001, **p < 0.01, *p < 0.05 vs. ORX; #p < 0.05 vs. enzalutamide.
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f4: Growth inhibition of VCaP cells in in vitro and in vivo CRPC settings.A. VCaP prostate cancer cells were treated with a submaximal concentration of mibolerone (0.1 nM) and different concentrations of test compounds in steroid-depleted medium, and cell growth was measured after 4 days of incubation using a WST-1 cell proliferation assay. The representative graph of the inhibitory effects of test compounds on the viability of VCaP cells is shown. All data points are means of quadruplicates ±SEM. IC50 values are presented in parentheses. B. Mean tumor volumes (mm3, +SEM) in castrated (ORX) nude mice with subcutaneous VCaP tumors after the oral treatment with ODM-201 (50 mg/kg, once or twice daily) or enzalutamide (20 mg/kg, once daily) for 37 days (n = 6−11). SHAM, sham-operated. ***p < 0.001, **p < 0.01, *p < 0.05 vs. ORX; #p < 0.05 vs. enzalutamide.

Mentions: To study the antiproliferative properties of ODM-201 and ORM-15341, we used the VCaP cell line originally derived from a bone metastasis of a CRPC patient. The VCaP cell line is characterized with endogenous AR gene amplification and AR overexpression30, typical for CRPC. When grown with a submaximal concentration of mibolerone, a synthetic androgen, ODM-201 and ORM-15341 suppressed androgen-induced cell proliferation more efficaciously than enzalutamide or ARN-509, IC50 values being 230 and 170 nM for ODM-201 and ORM-15341 vs. 410 and 420 nM for enzalutamide and ARN-509 (Fig. 4A). ODM-201 had no effect on the viability of AR-negative cell lines tested, DU-145 prostate cancer cells and H1581 lung cancer cells (Supplementary Fig. S3) confirming that the antiproliferative properties of ODM-201 and ORM-15341 are specific to AR-dependent PC cells.


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)

Growth inhibition of VCaP cells in in vitro and in vivo CRPC settings.A. VCaP prostate cancer cells were treated with a submaximal concentration of mibolerone (0.1 nM) and different concentrations of test compounds in steroid-depleted medium, and cell growth was measured after 4 days of incubation using a WST-1 cell proliferation assay. The representative graph of the inhibitory effects of test compounds on the viability of VCaP cells is shown. All data points are means of quadruplicates ±SEM. IC50 values are presented in parentheses. B. Mean tumor volumes (mm3, +SEM) in castrated (ORX) nude mice with subcutaneous VCaP tumors after the oral treatment with ODM-201 (50 mg/kg, once or twice daily) or enzalutamide (20 mg/kg, once daily) for 37 days (n = 6−11). SHAM, sham-operated. ***p < 0.001, **p < 0.01, *p < 0.05 vs. ORX; #p < 0.05 vs. enzalutamide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Growth inhibition of VCaP cells in in vitro and in vivo CRPC settings.A. VCaP prostate cancer cells were treated with a submaximal concentration of mibolerone (0.1 nM) and different concentrations of test compounds in steroid-depleted medium, and cell growth was measured after 4 days of incubation using a WST-1 cell proliferation assay. The representative graph of the inhibitory effects of test compounds on the viability of VCaP cells is shown. All data points are means of quadruplicates ±SEM. IC50 values are presented in parentheses. B. Mean tumor volumes (mm3, +SEM) in castrated (ORX) nude mice with subcutaneous VCaP tumors after the oral treatment with ODM-201 (50 mg/kg, once or twice daily) or enzalutamide (20 mg/kg, once daily) for 37 days (n = 6−11). SHAM, sham-operated. ***p < 0.001, **p < 0.01, *p < 0.05 vs. ORX; #p < 0.05 vs. enzalutamide.
Mentions: To study the antiproliferative properties of ODM-201 and ORM-15341, we used the VCaP cell line originally derived from a bone metastasis of a CRPC patient. The VCaP cell line is characterized with endogenous AR gene amplification and AR overexpression30, typical for CRPC. When grown with a submaximal concentration of mibolerone, a synthetic androgen, ODM-201 and ORM-15341 suppressed androgen-induced cell proliferation more efficaciously than enzalutamide or ARN-509, IC50 values being 230 and 170 nM for ODM-201 and ORM-15341 vs. 410 and 420 nM for enzalutamide and ARN-509 (Fig. 4A). ODM-201 had no effect on the viability of AR-negative cell lines tested, DU-145 prostate cancer cells and H1581 lung cancer cells (Supplementary Fig. S3) confirming that the antiproliferative properties of ODM-201 and ORM-15341 are specific to AR-dependent PC cells.

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