Mechanisms and targets in CRPC

The key for the development of new drugs and to optimize androgenic suppression in advanced stages of CRPC is the identification and characterization of molecular targets and mechanisms that lead to tumor growth. Disease progression involves the development of cellular adaptive pathways of survival in an androgen-depleted environment [34]. Experimental evidence assigns an important role to the continuous activation of the androgenic receptors (ARs) in tumor growth, as well as alternative independent routes [35]. In general, resistance mechanisms can be divided into 6 groups.

• Increased Expression of Enzymes Involved in Steroidogenesis. Studies have suggested that, in CRPC patients, even castrate serum levels of androgen are still sufficient for AR activation and able to maintain cancer cells survival. Indeed, the intratumoral levels of testosterone in CRPC patients are equal of those found in noncastrate patients [36]. The source of these androgens is thought to be derived from the synthesis of androgens directly in prostate cancer cells due to an upregulation of the enzymes and activation of the routes necessary for the synthesis of androgens such as testosterone and dihydrotestosterone [34, 37, 38]. Also bone metastases contain intact enzyme pathways for conversion of adrenal androgens to testosterone and dihydrotestosterone [36]. Montgomery and colleagues showed that there was marked reversal of the DHT: testosterone ratio in the metastatic tumor. These tumor cells express significantly lower levels of SRD5A2, which catalyses the conversion of testosterone to DHT, and higher levels of UGT2B15 and UGT2B17, which mediate the irreversible glucuronidation of DHT metabolites. Marked up regulation of CYP19A1, which mediates the aromatization of testosterone to estradiol, was also observed in the metastases samples [34, 36-38].

• Increased Expression of AR. The overexpression of AR have been involved in the progression of prostate cancer [34]. The activated AR pathways observed in these CRPC patients has been postulated as a result of genetic phenomena that promotes increased sensitivity of AR. DNA amplifications are responsible for AR overexpression and for its activation in presence of low levels of ligand (androgens) [34, 38].

• AR Gene Mutations and Altered Ligand Specificity. While the androgens are the main factors of tumor growth and AR signaling, the presence of AR mutations leads to its activation by nonandrogenic steroid molecules and antiandrogens [34]. The majority AR mutations are point mutations in the AR ligand-binding domain, and initially this was considered relevant to explain why 10-30% of patients receiving antiandrogens treatment experience paradoxical PSA drop on cessation of treatment [35]. However the AR mutations could occur in other regions such as the amino terminus or the DNA binding domain that confer oncogenic properties to the AR [37]. At the present, the role of AR mutations in the anti-androgen withdrawal phenomena is called into questioned and a new explanation is offered since the discovery of alternative splicing of the AR. In fact, in recent reports [39, 40], it was shown that splice variants of AR with deletion of exons 5, 6, and 7 could result in AR capable to translocate to the nucleus without ligand binding.

• Downstream Signaling Receptor for Androgens. One of the most important mechanisms in the development of castration resistance is the activation of different signal transduction pathways in CRPC cells. They could enhance the activity of the AR or its coactivators in the presence of low levels or even in the absence of androgen. These include other receptors such as epithelial growth factors, insulin growth factors, and tyrosine-kinase receptor [40].

• Bypass Pathways. The induction of bypass pathways independent of AR, is an important mechanism of castration resistance, that can overcame apoptosis induced by androgen-deprivation therapy. One such example of this is the up-regulation of antiapoptotic proteins, including the protein Bcl-2 gene [34, 40].

• Stem Cells. Prostatic cancer stem cells are rare and undifferentiated cells that do not express AR on their surface, being independent of androgens to survive [34]. Currently it is thought that these cells can be responsible for maintaining tumor growth and development, because they are able to survive under androgen-deprivation therapy. The identification of these cells is possible based on the expression of surface protein (a1f>1 integrin and CD133), which could allow new targets therapies [34].

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