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Targeting the adaptive molecular landscape of castration-resistant prostate cancer.

Wyatt AW, Gleave ME - EMBO Mol Med (2015)

Bottom Line: This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways.In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways.We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.

View Article: PubMed Central - PubMed

Affiliation: Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada awyatt@prostatecentre.com m.gleave@ubc.ca.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of androgen receptor reactivation in castration-resistant prostate cancerThe top left panel depicts the activation of the androgen receptor (AR) by its natural ligand (dihydrotestosterone, DHT) in a normal cell. Induction of functional tumour suppressors prevents the AR transcriptional program from driving mitogenesis. The top right panel shows adaptive and genomic changes in CRPC cells that can lead to direct reactivation of the AR in the absence of natural ligand. White boxes illustrate novel agents (targeted against AR reactivation) recently approved or currently undergoing clinical evaluation for the treatment of CRPC. The bottom panel demonstrates the contribution of AR co-factors and co-chaperones to the reactivation of AR in CRPC and illustrates novel targeting strategies in development.
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fig01: Mechanisms of androgen receptor reactivation in castration-resistant prostate cancerThe top left panel depicts the activation of the androgen receptor (AR) by its natural ligand (dihydrotestosterone, DHT) in a normal cell. Induction of functional tumour suppressors prevents the AR transcriptional program from driving mitogenesis. The top right panel shows adaptive and genomic changes in CRPC cells that can lead to direct reactivation of the AR in the absence of natural ligand. White boxes illustrate novel agents (targeted against AR reactivation) recently approved or currently undergoing clinical evaluation for the treatment of CRPC. The bottom panel demonstrates the contribution of AR co-factors and co-chaperones to the reactivation of AR in CRPC and illustrates novel targeting strategies in development.

Mentions: Ultimately, testosterone and DHT synthesis are dependent on catalytic conversion of cholesterol by members of cytochrome P450 (CYP) family of enzymes. CYP17A1 is a pivotal enzyme in this process, required for both canonical and alternative androgen synthesis, and has consequently been the focus of concerted drug development over the past decade (Fig1). This strategy was vindicated when phase III trials of the CYP17A1 inhibitor abiraterone acetate in metastatic CRPC (mCRPC) patients post- and pre-chemotherapy demonstrated an improved median overall survival (Fizazi et al, 2012; Ryan et al, 2013). The success of abiraterone has accelerated development of other CYP17A1 inhibitors, particularly compounds that specifically inhibit the 17,20-lyase activity of CYP17A1 and thereby render glucocorticoid co-admission unnecessary (Ferraldeschi et al, 2013). One such agent, orteronel (TAK-700; Kaku et al, 2011), was recently evaluated in two large phase III trials in mCRPC patients pre- and post-chemotherapy (NCT01193244; NCT01193257), but failed to demonstrate an overall survival benefit (Dreicer et al, 2014; Saad et al, 2015). These trials were likely confounded by post-study availability of abiraterone, and moreover, since both trials co-administered orteronel with prednisone, its vaunted 17,20-lyase specificity was not exploited. Two further next-generation CYP17A1 inhibitors, VT-464 (Toren et al, 2015) and galeterone (TOK-001) (Handratta et al, 2005) are currently undergoing phase I and II development, respectively (NCT02012920; NCT01709734) (Table1). VT-464 demonstrated anti-cancer activity in preclinical models of advanced CRPC, significantly lowering tumoural androgen levels in castrate mice, and enforcing greater suppression of the AR signalling axis compared to abiraterone (Toren et al, 2015). Galeterone showed promising phase I activity in chemotherapy-naïve CRPC patients (Taplin et al, 2012) and has the convenient side-effect of AR cross-inhibition.


Targeting the adaptive molecular landscape of castration-resistant prostate cancer.

Wyatt AW, Gleave ME - EMBO Mol Med (2015)

Mechanisms of androgen receptor reactivation in castration-resistant prostate cancerThe top left panel depicts the activation of the androgen receptor (AR) by its natural ligand (dihydrotestosterone, DHT) in a normal cell. Induction of functional tumour suppressors prevents the AR transcriptional program from driving mitogenesis. The top right panel shows adaptive and genomic changes in CRPC cells that can lead to direct reactivation of the AR in the absence of natural ligand. White boxes illustrate novel agents (targeted against AR reactivation) recently approved or currently undergoing clinical evaluation for the treatment of CRPC. The bottom panel demonstrates the contribution of AR co-factors and co-chaperones to the reactivation of AR in CRPC and illustrates novel targeting strategies in development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520654&req=5

fig01: Mechanisms of androgen receptor reactivation in castration-resistant prostate cancerThe top left panel depicts the activation of the androgen receptor (AR) by its natural ligand (dihydrotestosterone, DHT) in a normal cell. Induction of functional tumour suppressors prevents the AR transcriptional program from driving mitogenesis. The top right panel shows adaptive and genomic changes in CRPC cells that can lead to direct reactivation of the AR in the absence of natural ligand. White boxes illustrate novel agents (targeted against AR reactivation) recently approved or currently undergoing clinical evaluation for the treatment of CRPC. The bottom panel demonstrates the contribution of AR co-factors and co-chaperones to the reactivation of AR in CRPC and illustrates novel targeting strategies in development.
Mentions: Ultimately, testosterone and DHT synthesis are dependent on catalytic conversion of cholesterol by members of cytochrome P450 (CYP) family of enzymes. CYP17A1 is a pivotal enzyme in this process, required for both canonical and alternative androgen synthesis, and has consequently been the focus of concerted drug development over the past decade (Fig1). This strategy was vindicated when phase III trials of the CYP17A1 inhibitor abiraterone acetate in metastatic CRPC (mCRPC) patients post- and pre-chemotherapy demonstrated an improved median overall survival (Fizazi et al, 2012; Ryan et al, 2013). The success of abiraterone has accelerated development of other CYP17A1 inhibitors, particularly compounds that specifically inhibit the 17,20-lyase activity of CYP17A1 and thereby render glucocorticoid co-admission unnecessary (Ferraldeschi et al, 2013). One such agent, orteronel (TAK-700; Kaku et al, 2011), was recently evaluated in two large phase III trials in mCRPC patients pre- and post-chemotherapy (NCT01193244; NCT01193257), but failed to demonstrate an overall survival benefit (Dreicer et al, 2014; Saad et al, 2015). These trials were likely confounded by post-study availability of abiraterone, and moreover, since both trials co-administered orteronel with prednisone, its vaunted 17,20-lyase specificity was not exploited. Two further next-generation CYP17A1 inhibitors, VT-464 (Toren et al, 2015) and galeterone (TOK-001) (Handratta et al, 2005) are currently undergoing phase I and II development, respectively (NCT02012920; NCT01709734) (Table1). VT-464 demonstrated anti-cancer activity in preclinical models of advanced CRPC, significantly lowering tumoural androgen levels in castrate mice, and enforcing greater suppression of the AR signalling axis compared to abiraterone (Toren et al, 2015). Galeterone showed promising phase I activity in chemotherapy-naïve CRPC patients (Taplin et al, 2012) and has the convenient side-effect of AR cross-inhibition.

Bottom Line: This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways.In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways.We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.

View Article: PubMed Central - PubMed

Affiliation: Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada awyatt@prostatecentre.com m.gleave@ubc.ca.

No MeSH data available.


Related in: MedlinePlus