Grappling with the androgen receptor: a new approach for treating advanced prostate cancer
Grappling with the Androgen Receptor:A New Approach for TreatingAdvanced Prostate Cancer
Timothy C. 1Department of Genitourinary Medical Oncology, Research, Unit 18-3, The University of Texas M.D. Anderson Cancer Center,1515 Holcombe Boulevard, Houston, TX 77030, USA*Correspondence: DOI 10.1016/j.ccr.2010.05.018
In this issue of Cancer Cell, Andersen et al. report on a small molecule that interacts with and blocks trans-activation of the androgen receptor amino-terminal domain. This agent can overcome the shortcomings ofclinically used antiandrogens, an important advance in the development of effective therapy for advancedprostate cancer.
apy (ADT) for prostate cancer in the form
of estrogen treatment or surgical castra-
tion antiandrogen was built on the chemi-
lack of any significant toxicity associated
results of these initial studies were trans-
with administration of EPI-001 in preclin-
mutations in the LBD is not likely to occur
through the development of more effective
pharmacologic agents, including inhibitors
DNA binding, and coactivator recruitment;
proapoptotic activities; and lack of detect-
currently being tested in clinical trials (
interactions with the AR provide a molec-
of ADT and the exquisite sensitivity of the
independent AR activation through various
dent AR transactivation. It is interesting
express AR-splicing variants that lack the
(AR), as the premier therapeutic target for
suggesting that the molecular constraints
into a unique inhibitory gene profile. In
antagonists (bicalutamide, flutamide) that
turn, this suggests that additional experi-
interact with the carboxyl-terminal ligand-
The report by Andersen et al. in this issue
of Cancer Cell shows that EPI-001, which
is a BADGE (Bisphenol A Diglycidic Ether)
ment of so-called castrate-resistant pros-
come the ‘‘Achilles’ heel’’ of the antiandro-
that EPI-001 can block transactivation of
a constitutively active AR deletion mutant
prostate cancer cells render them insensi-
and hinge region, but not the LBD. In light
tive to ADT. CRPC is characterized partly
(AF)-1 region in the amino-terminal domain
(NTD) of the AR and does not interfere with
gens that target the LBD can lead to selec-
ligand binding. Additionally, EPI-001 does
to overstate the importance of this capac-
tion of prostate cancer cells that harbor AR
not inhibit the transcriptional activity of
mutations in the LBD. In some cases, these
mutations can cause prostate cancer cells
receptor. These results suggest that EPI-
001 is specific to the AR without inhibiting
Cancer Cell 17, June 15, 2010 ª2010 Elsevier Inc. 525
and represent a considerable threat to the
efficacy of currently used antiandrogens. Gain of function
EPI-001’s capacity to block transactivation
binding domain, and the hinge region, but
not the LBD, is a unique and critical func-
tion that will, we hope, have a substantialeffect in CRPC. Further studies that testadditional AR deletion mutants that contain
Constitutively Constitutively active deletion mutants
of this important and unique activity ofEPI-001. EPI-001 interactions
difficulties in the medical management ofadvanced prostate cancer. The molecular
and cellular interactions that contribute toprostate cancer growth, and its resistance
Figure 1. Potential of EPI-001 to Inhibit Specific Aberrant Androgen ReceptorTransactivation Activities that Contribute to Castrate-Resistant Prostate Cancer
(A) On the basis of its interaction with the AF-1 region of the AR amino-terminal domain (NTD), EPI-001
the bone microenvironment are just begin-
would not be expected to reduce the selection pressure for AR amplification and/or mutations in the
ning to be understood. However, it is a rare
AR NTD that are associated with CRPC. However, because EPI-001 does not interact with the ligand-
binding domain (LBD) or reduce ligand binding, it is unlikely that treatment would impose selection forgain-of-function LBD mutations that allow for AR-mediated activities in the presence of reduced or altered
peutic agent for advanced prostate cancer
(B) EPI-001 can block forskolin (FSK)- or IL-6-mediated ligand-independent AR transactivation activities.
is developed. We all wait with interest the
(C) EPI-001 can inhibit a constitutively active AR deletion mutant that lacks the LBD. P, possible AR phos-phorylation sites; filled rectangles, proteins that interact with AR to promote FSK- or IL-6–mediated ligand-
further preclinical and possible clinical
independent AR transactivation; DBD, DNA-binding domain; AF-1, activation function-1; AF-2, activation
testing of EPI-001 or its derivative(s).
function-2. AR protein domains are not drawn to scale.
the ligand-independent AR transactivation
I thank K.F. Phillips, ELS, and D.M. Walsh, MBA, fortheir expert editorial assistance.
showed that EPI-001 can also significantly
mediated by forskolin (FSK), which stimu-
reduce the weight of the prostate in intact
that no significant toxicity was observed.
Andersen, R.J., Mawji, N.R., Wang, J., Wang, G.,
Overall, these impressive results strongly
Haile, S., Myung, J.K., Watt, K., Tam, T., Yang,
support the therapeutic potential of EPI-
activation are poorly defined. In this regard,
Y.C., Banuelos, C.A., et al. (2010). Cancer Cell17, this issue, 535–546.
strated that EPI-001 inhibited interactions
Chen, Y., Sawyers, C.L., and Scher, H.I. (2008). Curr. Opin. Pharmacol. 8, 440–448.
inhibited N/C interactions through its inter-
Huggins, C., and Hodges, C.V. (1941). Cancer Res. 1, 293–297.
unique advantages of EPI-001 for inhibiting
CRPC. First, EPI-001’s capacity to interact
results have important therapeutic implica-
Nacusi, L.P., and Tindall, D.J. (2009). Expert Rev.
with and inhibit AR function without affect-
Endocrinol. Metab. 4, 417–422.
ing the LBD defines a new level of pharma-
Steinkamp, M.P., O’Mahony, O.A., Brogley, M.,
escape from EPI-001’s effects. Additional
Rehman, H., Lapensee, E.W., Dhanasekaran, S.,Hofer, M.D., Kuefer, R., Chinnaiyan, A., Rubin,
selection pressure for mutations in the AR
studies to analyze EPI-001’s capacity to
M.A., et al. (2009). Cancer Res. 69, 4434–4442.
Taplin, M.E., and Balk, S.P. (2004). J. Cell. Bio-
However, previous investigators have sug-
to address this issue and perhaps lead to
Tran, C., Ouk, S., Clegg, N.J., Chen, Y., Watson,P.A., Arora, V., Wongvipat, J., Smith-Jones, P.M.,
important information related to AR struc-
Yoo, D., Kwon, A., et al. (2009). Science 324,
testing of EPI-001 or its derivatives for the
Third, recent reports of the expression of
Van Dort, M.E., Robins, D.M., and Wayburn, B.
AR splicing variants lacking the carboxyl
(2000). J. Med. Chem. 43, 3344–3347.
tions in the AR LBD will likely clarify this
terminus, including the LBD, reveal a new
Vis, A.N., and Schroder, F.H. (2009). BJU Int. 104,
526 Cancer Cell 17, June 15, 2010 ª2010 Elsevier Inc.
Substance Abuse in Rural Pennsylvania: Present and FutureLaurie Roehrich, Ph.D., William Meil, Ph.D.,Jennifer Simansky, M.A., William Davis, Jr., M.A., and Ryan Dunne, M.A. This project was sponsored by a grant from the Center for Rural Pennsylvania, a legislative agency of the PennsylvaniaThe Center for Rural Pennsylvania is a bipartisan, bicameral legislative agency that serves as a resour
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