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.

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

“…These observations are further corroborated by genetic evidence from transgenic mouse models, suggesting that increased AR signaling in the prostate is linked to an increase in precancerous lesions [21]. Since elevated level of androgen causes enhancement of prostate cancer, reduction of circulating levels of androgens is central to the treatment of prostate cancer [22,23]. The most effective treatment for early-stage prostate cancer includes suppression of AR function either by blocking androgen signaling with the anti-androgens bicalutamide (Casodex) or flutamide or by inhibiting the conversion of testosterone to the potent androgen dihydrotestosterone (DHT) with finasteride [22].…”

“…It contains 1 mg/ml punicalagin, 0.97 mg/ml EA and anthocyanins [28]. Monomeric and oligomeric ellagitannins as PA were purified from fruit husk as previously reported and analyzed by HPLC and liquid chromatography electrospray ionization mass spectroscopy (LC-ESI/MS) (22). EA was purchased from Sigma Aldrich (St. Louis, MO).…”

“…Since elevated level of androgen causes enhancement of prostate cancer, reduction of circulating levels of androgens is central to the treatment of prostate cancer [22,23]. The most effective treatment for early-stage prostate cancer includes suppression of AR function either by blocking androgen signaling with the anti-androgens bicalutamide (Casodex) or flutamide or by inhibiting the conversion of testosterone to the potent androgen dihydrotestosterone (DHT) with finasteride [22]. However, 30% of these patients show relapse of the disease within 3 years as a result of the emergence of androgenindependent prostate cancer cells, which are either AR positive or AR negative [24,25].…”

Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

“…The kinase activity and protein expression data together strongly indicates a central involvement of both signalling pathways in the interaction between prostate carcinoma cells and osteoblasts. Additionally, given that EGFR and ERBB2 are phosphorylated in androgen-sensitive LNCaP cells upon influence of osteoblasts, a functional androgen signalling axis [16,17] may appear to be permissive for activity of these particular pathways in prostate cancer. Not the less, EGFR phosphorylation resulting from short-term incubation with bone stromal conditioned medium (containing 6% FBS) and suppression of in vivo bone metastasis formation following targeted inhibition of EGFR-dependent signalling have been demonstrated in androgen-independent prostate carcinoma PC3 cells [34].…”

“…Moreover, to simulate the complex processes involved in aberrant activation of the androgen signalling axis in prostate cancer [16,17], the experimental setup included LNCaP cells treated with the synthetic androgen analog R1881 to observe whether androgen receptor-mediated signalling pathways might differ from pathways activated by OHSdirected influence. Given the assumption that biologically relevant signalling events implicated in the metastatic phenotype require sustained activation, 48-h incubation times were used for the experimental LNCaP contexts.…”