Antiandrogens in the 21st century

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Jul 23, 2009 - such as nilutamide or bicalutamide (Casodex®), competitive reversible inhibitors of the androgen receptor (AR), this combina- tion results in ...
[Cancer Biology & Therapy 8:17, 1611-1611; 1 September 2009]; ©2009 Landes Bioscience Running title

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Antiandrogens in the 21st century Stephen T. Pisle and William D. Figg Molecular Pharmacology Section; Medical Oncology Branch; National Cancer Institute; NIH; Bethesda, MD USA

Abbreviations: PCa, prostate cancer; ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castrate resistant prostate cancer; SAR, structural activity relationship; PSA, prostate specific antigen; TMPRSS2, transmembrane serine protease 2 Key words: prostate cancer, androgen deprivation therapy, antiandrogen

Prostate cancer (PCa) is the second most common cause of cancer-related death among men, with around 218,000 new cases annually and 27,000 deaths. Most prostate cancer is hormone dependent and is treated with androgen deprivation therapy (ADT) such as Lupron or Abarelix (Plenaxis®) which block the production of testosterone in the testes. When combined with an antiandrogen such as nilutamide or bicalutamide (Casodex®), competitive reversible inhibitors of the androgen receptor (AR), this combination results in complete androgen blockade (CAB).1 If the disease progresses to castration-resistant prostate cancer (CRPC) CAB is no longer effective; this failure of therapy is commonly associated with increased levels of AR expression,2 through various mechanisms, which have been shown in mouse xenograft models to be necessary and sufficient to confer resistance to antiandrogen therapy.3 Tran and Ouk et al. have recently published a paper characterizing two novel antiandrogens, RD162 and MDV3100, which retain activity even under increased androgen expression that is seen in most CRPC. These two nonsteroidal antiandrogens were derived through a structural activity relationship (SAR) study, based on the starting molecule RU59063, a non-steroidal small molecule with high affinity and selectivity for the AR. After screening over 200 compounds, RD162 and MDV3100 were selected due to superior serum half-life, oral bioavailability, and AR antagonist activity.4 The reasoning used in the development of RD162 and MDV3100 can be used for the creation of small molecule analogues to known enzyme and receptor inhibitors to improve upon current therapeutic regimens. Chemical screenings that look at inhibitory activity without regard to pharmacokinetic properties are limited as they may identify a large number of molecules that would not be able to be fully developed due to bioavailability and formulation issues. Assessment of moieties that are not vital for drug binding can be altered to increase serum half-life and bioavailability, resulting in an increase in drug exposure. *Correspondence to: National Cancer Institute; Medical Oncology Branch; 9000 Rockville Pike; Bldg. 10, Room 5A01, MSC 1910; Bethesda, MD 20892 USA; Tel.: 301.402.3622; Fax: 301.402.8606; Email: [email protected] Submitted: 7/23/09; Accepted: 7/24/09

RD162 and MDV3100 suppress growth of PCa cell lines in vitro and in vivo, with a decrease in tumor volume compared to bicalutamide in an AR overexpressing cell line. A benefit was also seen with an increase in median times to progression of 151 d for RD162 compared to bicalutamide. Tumor response was also seen in MDV3100 treated mice, as well as in a hormone refractory cell line, LNCaP/HR, derived from serial passage in castrated male mice.4 LNCaP/HR simulates CRPC more closely because it is not a forced overexpression of AR. Aside from the loss of antagonist activity of the first generation antiandrogens, bicalutamide and flutamide, in most CRPC a partial agonism has been observed, with patients having an antiandrogen withdrawal response resulting in a decline in prostate specific antigen (PSA) after discontinuing treatment once disease progression has occurred.5 An in vitro experiment, employing the LNCaP/ AR cell line, examined AR target genes PSA and transmembrane serine protease 2 (TMPRSS2) upon treatment with bicalutamide, RD162, or MDV3100; induction of PSA and TMPRSS2 was only seen with bicalutamide treatment. This suggests that RD162 and MDV3100 do not possess agonist activity in CRPC. Further evidence is gained from in vitro experiments in which RD162 and MDV3100 decreased nuclearization of AR as well as directly impaired AR DNA binding when compared to both an AR agonist and bicalutamide.4 The early phase I/II clinical trial results for MDV3100 show 13 of 30 patients with CRPC having sustained declines of PSA by greater than 50 percent.4 Though this is preliminary data and more clinical studies are needed, MDV3100 looks promising in the treatment of CRPC, which to date has limited treatment options. References 1. Rugo Hope S, “Chapter 39. Cancer” (Chapter). McPhee SJ, Papadakis MA, Tierney LM, Jr.: Current Medical Diagnosis & Treatment 2009: http://www.accessmedicine.com/ content.aspx?aID=21374. 2. Scher, H. I. and C. L. Sawyers (2005). “Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis.” J Clin Oncol 23(32): 8253-61. 3. Chen, C. D., D. S. Welsbie, et al. (2004). “Molecular determinants of resistance to antiandrogen therapy.” Nat Med 10(1): 33-9. 4. Tran, C., S. Ouk, et al. (2009). “Development of a second-generation antiandrogen for treatment of advanced prostate cancer.” Science: 1168175. 5. Hiroshi, M., M. R. Mujib, et al. (2004). “Molecular basis for the antiandrogen withdrawal syndrome.” Journal of Cellular Biochemistry 91(1): 3-12.

Previously published online as a Cancer Biology & Therapy E-publication: www.landesbioscience.com/journals/cbt/article/9617

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