Improving the outcome of patients with castration-resistant prostate cancer through rational drug development

Abstract

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease.

Figure 1

Treatment flow chart for patients diagnosed with CRPC.

Figure 2

Novel therapeutic targets and proposed mechanisms of androgen resistance (text in red) in hormone refractory prostate cancer. (1) Hypersensitive Pathway: AR amplification, increased AR expression or alterations in corepressor/coactivator function. (2) Versatile receptor: mutations in the ligand-binding domain of the AR permitting nonandrogenic ligand binding. (3) Alternative routes: utilisation of AR machinery by alternative pathways, that is, PI3K/Akt. (4) Bypass pathways: bypassing of the AR and its cellular machinery entirely, that is, upregulation of the antiapoptotic protein Bcl-2. Therapeutic targets include: the adrenal steroid synthesis pathway, AR signalling, growth factor receptors (GFR), PTEN (phosphatase and tensin homolog) and PI3K (phosphatidylinositide 3-OH kinase) signalling, angiogenesis and apoptosis. HSP90 denotes heat shock protein 90; PIP2 phosphatidylinositol-4,5- bisphosphate; PIP3 phosphatidylinositol-3,4,5- triphosphate; Akt protein kinase B; mTOR mammalian target of rapamycin; oncogenes Ras, Raf, Mek, Erk; Bcl-2 antiapoptotic protein; APAF1 apoptotic peptidase activating factor 1; IAP inhibitor of apoptosis family (of which survivin is a member). Solid lines indicate promotion. Broken lines indicate inhibition.