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Treatment resistance in prostate cancer: Rationale of combination therapy (85.2)
Author(s) -
Zoubeidi Amina
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.85.2
Subject(s) - enzalutamide , prostate cancer , androgen receptor , lncap , medicine , cancer research , epithelial–mesenchymal transition , cancer , androgen deprivation therapy , oncology , metastasis
Despite advances in targeting the androgen receptor in prostate cancer patients which have led to unprecedented improvements in both overall survival and disease free, challenges still remain. Recently FDA approved second generation anti‐androgen Enzalutamide (ENZ) has limited efficacy in a substantial percentage of men and even those showing dramatic responses still develop resistance. These clinical results underscore the importance of understanding the mechanisms of resistance to ENZ. As seen in patients, we found that the resistance also occurs in our preclinical LNCaP xenograft model; the maximum androgen blockade (castration plus ENZ) leads to cancer recurrence in 80% of the ENZ treated tumors while only 20% responded to treatment. Targeting the AR in ENZ resistant tumors with a 3rd generation AR inhibitor was short lived. These data highlight that unexplored signalling pathways drive treatment resistance beyond classical AR reactivation underscore the need of more effective therapies. Using unbiased approaches of gene profiling and sequencing, we found that resistance is heterogeneous and displays cell plasticity indicating the existence of the epithelial cells driven by AR, the emergence of cancer stem cells (CSCs) and cells that may have progressed through an epithelial‐to mesenchymal transition (EMT). We will discuss the involvement of oncogenic and survival pathways driving the resistance as well as the rational of co‐targeting therapy to enhance the efficacy of Enzalutamide for better and long anti‐cancer response. This work is supported by Prostate Cancer Canada Movember Team grant, Prostate Cancer Foundation USA and NCI SPORE Pilot grant