Nonandrogen regulated transcription factors in prostate cancer rationale for targeting

Most targeted small molecule therapies under development interfere with the function of receptors on the cell surface or kinases located in the cytoplasm. Transcription factors have been underutilized as targets of cancer therapeutics, the exceptions being the steroid hormone receptors, such as the AR, and nuclear factor kappa B (NF- " B) [8, 9]. However, it is imperative to identify novel targets for the design of molecular treatments for cancers, including AIPC. Advances in drug delivery systems and a better understanding of how transcription factors act should overcome issues with targeting this important group of proteins. Thus, we believe that effective therapeutics for AIPC can be developed by identifying and targeting key transcriptional regulators, other than the AR, that are required for prostate cancer proliferation and survival. To identify potential targets that are master transcriptional regulators, one looks for DNA binding proteins whose activity is required for cell fate decisions, stem cell homeostasis, proliferation, and development. The regulatory roles played by Core Binding Factor (CBF) [10] and CBF1, Suppressor of Hairless, Lag-1 (CSL), the downstream effector of Notch receptors, place these transcription factors at the pinnacle of signaling cascades required for malignancy [11, 12]. Perhaps not surprisingly, these two pathways are genetically linked and exhibit cross talk. For example, enforced expression of RUNX1 rescues the Notch1-null phenotype in zebrafish [13] and in Notch1-null mice RUNX1 expression is greatly reduced [14]. Moreover, Notch and RUNX1 cooperate during T-cell specification in mammals and CBF is required for pre-thymic cells response to Notch signaling [15]. Thus, these two important transcriptional pathways are linked and, together, present a number of novel targets for the development of cancer therapies.

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