Current therapy implications and future directions

The reciprocal interactions and interplay between the AR and PI3K/AKT axis suggests that the underlying mechanism potentiating CaP progression is complex and impacts the very balance of these prosurvival pathways. Current literature shows that there is indeed crosstalk between the AR and PI3K/AKT pathway occuring at various levels. The integration of these oncogenic pathways potentiates CaP tumorigenesis and this is further complicated by the levels of androgens and stage of CaP progression. In effect, the transition from AD-CaP to AI-CaP in prostate carcinogenesis provides major clinical challenges. Androgen ablation and/or anti-androgen therapies are only temporarily effective. Such therapies yield a hormone refractory tumor that is essentially untreatable with the most effective standard chemotherapeutic regimens which only increase patient survival for 2 months [191]. In this case, the pharmacological challenge then, will be to consider the contributions from both PI3K/AKT and AR signalling pathways throughout CaP progression [82].

The mTORCl pathway has been a primary focus for drug development due to the discovery of rapamycin [93]. However, selective inhibitors from this family of compounds have not proven to be effective. Although, it seems promising to use drug combinations for the inhibition of the main survival pathways (mTORCl, PI3K, AKT) this may incidently result in high toxicity. The concept of intercepting signaling cross-talk with drug combinations to target multiple nodes of integration and/or multiple kinases may be useful in controlling upstream and downstream the PI3K pathway. In addition, the ability of the PI3K/AKT pathway to synergistically heighten AR signaling together with non-genomic cross talk between other pro-survival factors make targetable areas for therapy difficult. Now, with the integration of the Wnt/p-catenin signalling pathway in AR regulation the interplay between PI3K, Wnt and AR signaling becomes further complicated. As such, putative chemotherapeutic agents that inhibit upstream the Wnt or PI3K signaling may pose a viable option [194].

The oncogenic role of the PI3K/AKT pathway in CaP progression is clearly evident. However, the mechanisms underlying the interplay between PI3K and AR signaling still remains unclear. Therefore, understanding how crosstalks are regulated in CaP progression will provide a means by which to elucidate the complexities and contexts of AI disease that are necessary for successful therapeutic intervention.

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