Androgen receptor as a therapy target in hormoneresistant prostate cancer

Currently there is no efficient method available to treat patients who relapse during androgen ablation therapy and develop an androgen-independently growing tumor. Based on an improved understanding of AR signaling in therapy-refractory prostate cancer, novel therapies are being developed that target AR in advanced tumor cells.

Specific antisense AR oligonucleotides were identified that inhibit AR expression. Treatment of such prostate cancer cells resulted in reduced androgen receptor levels, growth inhibition and reduced PSA production in vitro and in vivo (Eder etal. 2000; 2001). Another approach is the use of derivatives of the antibiotic geldanamycin that

Table 2.1 Promiscuous mutant androgen receptors in prostate cancer

Amino acid

Promiscuous

position

Mutation

Description

Activation

References

670

Glu^Arg

• Primary tumor of

Progesterone

(Buchanan et al. 2001;

untreated patient

Adrenal androgens

Tilley etal. 1996)

• Mutation in the AR

Hydroxyflutamide

hinge region

715

Val^Met

• Primary tumor of

Progesterone

(Culig etal. 1993;

hormone-refractory

Adrenal androgens

Peterziel etal. 1995)

patient

DHT metabolites Hydroxyflutamide

726

• Overrepresented in Finnish PCa patients

Estradiol

(Elo etal. 1995; Mononen et al. 2000)

730

Arg^Leu

• Primary tumor

DHT metabolites Hydroxyflutamide

(Newmark etal. 1992; Peterziel et al. 1995)

874

His^Tyr

. CWR-22 PCa

DHEA

(Bubley etal. 1996;

xenograft derived

Estradiol Progesterone

Shao et al. 2003; Tan

from a bone

Hydroxyflutamide

etal. 1996; Taplin

metastasis

etal. 1995)

877

Thr^Ser

Progesterone

Hydroxyflutamide

(Bubley etal. 1996; Taplin et al. 1995)

877

Thr^Ala

• LNCaP cell line

Estradiol

(Gaddipati etal. 1994;

derived from lymph

Progesterone

Grigoryev et al. 2000;

node metastasis

Hydroxyflutamide

Suzuki etal. 1996;

• Several tumor

Pregnenolone

Suzuki etal. 1993;

specimens

Veldscholte et al.

• Mutation hot spot in

1990a; Veldscholte

hormone-refractory

etal. 1992a)

tumors

877 701

Thr^Ala

• Double mutation

Cortisol

(Krishnan et al. 2002;

Leu^ His

• MDA PCa 2b cell line

Corticosterone

Matias et al. 2002;

derived from tumor

C17, C19 and

Zhao etal. 1999;

metastasis

C21 steroids

Zhao et al. 2000)

• Androgen activation

decreased

Of the about eighty androgen receptor gene mutations detected in prostate cancer specimens only some have been analyzed in terms of their functional consequences. Most of these mutations result in promiscuous androgen receptors that, in addition to androgens, are activated by other steroids and/or the antiandrogen hydroxyflutamide. The table lists AR mutations showing promiscuous activation. For a complete list of all AR mutations detected in prostate cancer, see the AR database web site (www.mcgill.ca/androgendb).

interfere with the function of heat shock protein Hsp90 and results in destabilization anddegradation of proteins dependent on Hsp90, among them Her-2/Neu receptor and the androgen receptor (Morris and Scher 2000; Solit etal. 2002).

Growth factors stimulate cell proliferation and cell survival through activation of the MAP kinase cascade that in turn induces ligand-independent AR stimulation. Therefore, another strategy is the direct inhibition of cell membrane receptors. Burfeind and coworkers, for example, suggested that targeting the IGF-I receptor maybe a potential treatment for prostate cancer (Burfeind etal. 1996). Membrane receptors, especially those of the EGF receptor family have also been targeted using specific monoclonal antibodies. The EGF receptor seems to be a central component in MAP kinase signaling in prostate tumor cells and provides a valuable target for a therapeutic strategy (Putz etal. 1999). EGF receptor blocking antibodies and inhibitors of EGF receptor kinase have already entered clinical trials (Ciardello and Tortora 1998; Herbst 2002; Trump etal. 2002). Craft etal. (1999a) reported on the effects of monoclonal antibodies blocking the HER-2/neu receptor, another member of the EGF receptor family. This antibody had considerable tumor-inhibiting effects and well-tolerated toxicity in prostate cancer patients. Finally, inhibition of prostate tumor cells was demonstrated by antisense depletion of cyclic AMP-dependent protein kinase (PKA) that also plays a role in ligand-independent activation of the AR (Nesterova and Cho-Chung 2000).

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