Beyond the Abstract - Direct regulation of androgen receptor activity by potent CYP17 inhibitors in prostate cancer cells, by Przemyslaw Twardowski, MD and C.A. Stein, MD, PhD

BERKELEY, CA (UroToday.com) - Androgen deprivation therapy for the management of advanced prostate cancer remains one of the most durable discoveries in medical oncology, and continues to undergo refinement as our knowledge of the nuances of androgen-androgen receptor (AR) pathway expands.

Treatment with orchiectomy or LHRH agonist/antagonists results in the removal of the testicular source of testosterone but does not address the ongoing production of androgens in the adrenal gland and tumor tissue that contribute to persistent stimulation of androgen receptor. The antifungal compound ketoconazole inhibits cholesterol side chain cleavage (11-β hydroxylase activity) and CYP17 enzymes, both important in the synthesis of testosterone.(1) It has shown definitive activity against prostate cancer, associated with declines in the serum androgen precursors dihydroepiandrosterone (DHEA) and androstenedione.(2)However, ketoconazole is a relatively weak inhibitor of CYP17 and is notorious for significant drug interactions due to its inhibitory effect on the CYP3A4 metabolizing enzyme, making it challenging in clinical use.

 

"With the clinical success of abiraterone, the question before the prostate cancer drug development community now is: Where do we go from here?"

More discriminate targeting of androgen biosynthesis has been the focus of recent drug development. Abiraterone is a selective CYP17 inhibitor with an approximately 10-fold increase in potency over ketoconazole. In phase II studies, it has induced dramatic declines in serum testosterone to undetectable levels and shown impressive clinical activity in patients with castration resistant prostate cancer (CRPC) regardless of prior exposure to chemotherapy.(3) A subsequent phase III study (COU-301) randomized patients with disease progression after a docetaxel-based regimen to receive abiraterone plus prednisone or placebo plus prednisone, with treatment continuing until disease progression. The results from this study demonstrated improvement in overall survival from 10.9 to 14.8 months, with a hazard ratio of 0.646.(4) An additional phase III study, exploring the effects of abiraterone in patients not yet treated with chemotherapy, has completed accrual. Abiraterone is well tolerated, with its main side effects related to the mineralocorticoid hormone excess resulting from “diversion” of the precursors of testosterone synthesis into the mineralocorticoid pathway. These side effects are usually ameliorated by the use of low doses of prednisone. Abiraterone does not significantly inhibit CYP3A4 and is not associated with drug interactions that plague the use ketoconazole. TAK-700, a non-steroidal next-generation CYP17 inhibitor, is currently undergoing phase III clinical trials that closely recapitulate the clinical development of abiraterone.(5)

With the clinical success of abiraterone, the question before the prostate cancer drug development community now is: Where do we go from here? For as noted above, the sad truth is that in the cohort of patients who have failed docetaxel (and despite the fact that a relatively small number of patients do particularly well), CYP17 inhibition provides an increase in overall survival of somewhat less than 5 months, and no patient will be cured of this disease by this drug. However, even though post-abiraterone patients eventually become resistant to CYP17 inhibition, it is still probably true, as extensively noted in a recent review by Peter Nelson,(6) that their disease remains AR dependent. One way this could happen is through alternative splicing of the AR mRNA that deletes the AR androgen-binding domain.(7) This appears to cause constitutive receptor activation, that is, translocation of the AR from the cytoplasm to the nucleus, and the activation of pro-metastasis, pro-invasion, pro-growth, and anti-apoptotic genes by the mutant AR. None of our current therapies address the problem of the androgen-independent constitutively active AR: What we as genitourinary oncologists really need our synthetic chemist and drug development colleagues to provide us a drug that inhibits CYP17 activity and downregulates the AR simultaneously, at low concentration, and with minimal toxicity. A good start in this direction has been made with galeterone (TOK-001), which appears to do both, as described in the JBC paper, although the mechanism of the downregulation of the AR protein by this drug appears to be non-specific.

So what do the JBC data really mean in the clinic? One problem is that of prostate cancer cellular variability and hence differential responsiveness to drugs. For example, the galeterone concentrations resulting in maximal AR protein downregulation can be approximately 15 mM in LNCaP cells, although in LAPC-4 cells, only 1-2.5 mM appear to be required. On the other hand, because these very hydrophobic 17-hydroxarylsteroids appear to be accumulated in steroidogenic tissues, longer drug exposures at lower concentrations may ultimately produce similar outcomes to exposure at high plasma concentrations.

Clearly, though, our experiments demonstrate that although abiraterone alcohol, the pharmacologically active ingredient in the drug marketed as Zytiga, and galeterone are structurally similar, they have markedly different properties in tissue culture experiments, and presumably will in vivo as well. However, even though both 17-heteroarylsteroids share the ability to cause significant downregulation of the expression of the AR protein in cultured cells, it is not clear that the way they accomplish this is identical. The extent to which in vivo downregulation of AR expression will occur is also uncertain. While there is evidence from recently published work(8) that AR protein expression can be downregulated by galeterone but not abiraterone in human tumor xenografts in nude mice, only a single human prostate cancer cell line (LAPC-4) was employed in that work. Much additional experimentation, including immunohistochemical studies, is underway to convincingly demonstrate that in vivo AR downregulation is a general in vivo property of TOK-001. Finally, drug concentrations that would be necessary for maximal downregulation of AR protein expression in clinical prostate cancer can only be guessed at, and may or may not be attainable pharmacologically. The analysis of biopsy samples obtained from patients entered into clinical trials with galeterone will hopefully be able to shed some light on this interesting and important question.

 

References:

  1. Haidar S, Ehmer PB, Barassin S, et al.: Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P45017, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 84:555-562, 2003
  2. Trump DL, Havlin KH, Messing EM, et al.: High-dose ketoconazole in advanced hormone refractory prostate cancer: Endocrinologic and clinical effects. J Clin Oncol 7:1093-1098, 1989
  3. Attard G, Reid AH, A’Hern R, et al.: Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 27:3742-3748, 2000
  4. de Bono JS, Logothetis CJ, Scher HI, et al.: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011 May 26;364 (21):1995-2005
  5. Agus DB: Safety, efficacy, and pharmacodynamics of the investigational agent TAK-700 in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study. J Clin Oncol 29:296s, 2011 (suppl; abstr 4531)
  6. Nelson, P. Molecular states underlying androgen receptor activation: A framework for therapeutics targeting androgen signaling in prostate cancer. J Clin Oncol 30:644-646, 2012
  7. Sun, S. Sprenger, C., Vessella, R., et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120:2715-2730, 2010.
  8. Bruno, R., Vasaitis, T., Gediya, L., et al. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids 76:1268-1279, 2011

 


 

Written by:
Przemyslaw Twardowski, MD and C.A. Stein, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Department of Medical Oncology and Experimental Therapeutics
City of Hope National Medical Center
1500 E. Duarte Road
Duarte, CA USA
91010

Direct regulation of androgen receptor activity by potent CYP17 inhibitors in prostate cancer cells - Abstract

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