2008;68:4447C4454. kinase pathways. This has Rabbit Polyclonal to MRPS21 led to the development of a number of novel agents targeting AR signaling pathway, including more effective antiandrogens, inhibitors of CYP17, an enzyme required for androgen synthesis, inhibitors of 5-reductase, inhibitors of HSP90 which protects AR from degradation, inhibitors of histone deacetylases which is required for optimal AR mediated transcription, as well as inhibitors of tyrosine kinase inhibitors. Many of these strategies are currently being tested in clinical trials in CRPC. Introduction The androgen receptor (AR), located on Xq11-12, is usually a 110 kD nuclear receptor that, upon activation by androgens, mediates transcription of target genes that modulate growth and differentiation of prostate epithelial cells. AR signaling is crucial for the development and maintenance of male reproductive organs including the prostate gland, as genetic males harboring loss of function AR mutations and mice designed with AR defects do not develop prostates or prostate malignancy [1,2]. This dependence of prostate cells on AR signaling continues even upon neoplastic transformation, leading to the seminal discovery by Huggins and Hodges in 1941 that orchiectomy produced prostate malignancy regression [3]. Androgen depletion (now using GnRH agonists) continues to be the mainstay of prostate malignancy treatment. However androgen depletion is usually effective for a limited duration and prostate malignancy evolves to regain the ability to grow despite low levels of circulating androgens [4]. Treatment options for castration resistant prostate malignancy (CRPC) are an unmet need with docetaxel being the only agent that has been shown to prolong survival [5,6]. Interestingly, while a small minority of CRPC does bypass the requirement for AR signaling [7], the vast majority of CRPC, though frequently termed androgen independent prostate cancer or hormone refractory prostate cancer, retains its lineage dependence on AR signaling. Over the past several years, several important mechanisms of Manitimus enhanced AR signaling in low serum androgen levels in CRPC have been elucidated. This has led to novel therapeutic strategies targeting AR signaling which offer promising potential in future treatment of CRPC (Figure 1). Open in a separate window Figure 1 Schematic of therapeutic targets of Manitimus the AR pathway. 1) AR is bound to the molecular chaparonin HSP90 which prevents its degradation. HSP90 inhibitors, such as 17-AAG, cause AR degradation and decrease AR levels. 2) In men treated with GnRH agonists to shut down testicular androgen synthesis, residual serum androgens are synthesized by the adrenal glands. In additional, evidence suggests intratumoral androgen synthesis. Both can be inhibited by the non-specific p450 inhibitor ketoconazole and the 17-lyase inhibitor abiraterone. 3) Testosterone is converted to the more potent dihydrotestosterone (DHT) by 5-reductase, which is inhibited by finasteride and dutasteride. 4) Ligands, such as DHT bind to AR and this is inhibited by antiandrogens such as bicalutamide and novel agents MDV-3100 and BMS641988. Mutation of AR as well as AR overexpression can convert endogenous steroids (e.g., progestins, estrogens, corticosteroids) and some antiandrogens into agonists. MDV-3100 was designed to suppress AR function even when AR is overexpressed. 5) Activation of receptor tyrosine kinases, in particular HER2, can lead to downstream AR activation. Two downstream kinases that directly phosphorylate AR on tyrosine are Ack1 and SRC. Other downstream pathways of receptor tyrosine kinases, including the AKT and MAP kinase pathways, are also implicated. Antibodies such as trastuzamab and pertuzumab and small molecular TKI inhibitors such as erlotinib and lapatinib target HER2. Dasatinib target SRC. 6) Proper transcription mediated by AR requires the proper chromatin state. HDAC inhibitors inhibit transcription of AR target genes by disruption of chromatin structure and inhibition of recruitment of coactivators and RNA polymerase II. Castration resistant prostate cancer requires AR signaling Several clinical observations have long offered clues that AR signaling is active and required in most CRPC. PSA, an exquisitely AR dependent gene, is widely used Manitimus as a marker for disease activity. PSA declines after initiation of hormone depletion therapy and a subsequent rise is commonly the first sign of disease progression. This indicates that reactivation of AR signaling accompanies the development of CRPC. Both the relative and absolute level of PSA declinemarkers of the degree of AR inhibitionafter initial androgen depletion is predictive of outcome [8]. After development of castration resistance, further hormonal manipulations targeting AR can elicit response while treatment with Manitimus exogenous androgens usually results in tumor flare. First demonstrated for flutamide, treatment with any currently available antiandrogen may result in agonist Manitimus conversion, and tumor response can be observed upon andiandrogen withdrawal (AAWD) [9]. Gene expression studies of clinical prostate cancer specimens show that AR activated genes (defined as genes down-regulated after.