Shan Wang1, Dede N Ekoue2, Ganesh V Raj3, Ralf Kittler4. 1. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Shan.Wang@utsouthwestern.edu. 2. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA. 4. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Ralf.Kittler@utsouthwestern.edu.
Abstract
The current therapeutic armamentarium for castration-resistant prostate cancer (CRPC) includes second-generation agents such as the Androgen Receptor (AR) inhibitor enzalutamide and the androgen synthesis inhibitor abiraterone acetate, immunotherapies like sipuleucel-T, chemotherapies including docetaxel and cabazitaxel and the radiopharmaceutical radium 223 dichloride. However, relapse of CRPC resistant to these therapeutic modalities occur rapidly. The mechanisms of resistance to these treatments are complex, including specific mutations or alternative splicing of oncogenic proteins. An alternative approach to treating CRPC may be to target the turnover of these molecular drivers of CRPC. In this review, the mechanisms by which protein stability of several oncoproteins such as AR, ERG, GR, CYP17A1 and MYC, will be discussed, as well as how these findings could be translated into novel therapeutic agents.
The current therapeutic arman class="Species">mentarium for castration-resistant prostate cancer (CRPC) includes second-generation agents such as the Androgen Receptor (AR) inhibitor enzalutamide and the androgen synthesis inhibitor abiraterone acetate, immunotherapies like sipuleucel-T, chemotherapies including docetaxel and cabazitaxel and the radiopharmaceutical radium 223 dichloride. However, relapse of CRPC resistant to these therapeutic modalities occur rapidly. The mechanisms of resistance to these treatments are complex, including specific mutations or alternative splicing of oncogenic proteins. An alternative approach to treating CRPC may be to target the turnover of these molecular drivers of CRPC. In this review, the mechanisms by which protein stability of several oncoproteins such as AR, ERG, GR, CYP17A1 and MYC, will be discussed, as well as how these findings could be translated into novel therapeutic agents.
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Authors: C Parker; S Nilsson; D Heinrich; S I Helle; J M O'Sullivan; S D Fosså; A Chodacki; P Wiechno; J Logue; M Seke; A Widmark; D C Johannessen; P Hoskin; D Bottomley; N D James; A Solberg; I Syndikus; J Kliment; S Wedel; S Boehmer; M Dall'Oglio; L Franzén; R Coleman; N J Vogelzang; C G O'Bryan-Tear; K Staudacher; J Garcia-Vargas; M Shan; Ø S Bruland; O Sartor Journal: N Engl J Med Date: 2013-07-18 Impact factor: 91.245