New Mechanism Based Approaches For Treating Prostate Cancer
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New Mechanism Based Approaches for Treating Prostate Cancer
Author | : Rayna Rosati |
Publisher | : |
Total Pages | : 231 |
Release | : 2017 |
Genre | : Oncology |
ISBN | : |
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Prostate cancer (PC) is generally dependent on the androgen signaling axis for tumor growth. PC is managed by androgen deprivation therapy (ADT). The tumors then frequently progress by restoring ADT-resistant AR signaling through mechanisms such as intratumoral androgen synthesis, overexpression of AR, expression of splice variants of AR and alteration in the balance of AR co-regulators. This stage of progression is termed castrate recurrent prostate cancer (CRPC). Moreover, ADT has many major undesirable acute and chronic side effects on various normal tissues. Therefore a more strategic therapy approach is one that would disrupt a functional arm of AR signaling critical for PC/CRPC growth but not for the essential physiological roles of AR in normal adult tissues. This thesis describes two different mechanism-based approaches to develop small molecule drugs that address the above problems. The transcription factor ELK1 tethers the androgen receptor (AR) to chromatin, enabling sustained activation of genes critical for growth in prostate cancer cell lines. The N-terminal A/B domain of AR [AR(A/B)], which excludes the ligand binding pocket of AR, is adequate for interaction with ELK1. This is significant because the major splice variants of AR (AR-V7) that lack the ligand binding domain, as well as overexpressed full length AR, are known to strongly support growth of castration resistant prostate cancer (CRPC). In our first approach to develop small molecule drugs for prostate cancer, we showed that both wtAR and AR-V7 synergize with ELK1 by coopting the two ERK docking sites on ELK1, independent of the classical mechanism of (transient) activation of ELK1 via phosphorylation by ERK. As the association of ELK1 and AR is only required for prostate tumor growth, disrupting this interaction should selectively inhibit the growth of CRPC cells without interfering with the physiological role of androgen in normal tissues.
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