Developing Novel Therapeutics for Endocrine Cancers

P160 Steroid Receptor Coregulators as Novel Therapeutic Agents

Functional outputs of steroid receptors can be greatly modulated by steroid receptor coactivators. The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 (also known as TIF2, GRIP1, and NCOA2), and SRC-3 (also known as AIB1, ACTR, and NCOA3) are key pleiotropic “master regulators” of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. The SRCs can integrate input from other signaling cascades, allowing for cross-talk with other growth and survival pathways (e.g. kinases/phosphatases, acetyltransferases/deacetylases, etc) that can regulate SRC protein stability and activity, allowing for enormous plasticity of the steroid hormone signal but also for numerous mechanisms of signal amplification in a ligand-independent manner.

SRC over-expression and over-activation occur in numerous human cancers due to a variety of genomic, transcriptional, and post-translational mechanisms, and are associated with poor clinical outcomes and resistance to therapy, suggesting that the SRCs are important therapeutic targets. Surprisingly, the field has noted that often time over-expression and over-activation of SRC (for examples, SRC-3 in prostate cancer) occurs without gene amplifications or mRNA over-expression. Yet, much of the mechanisms underlying over-expression and over activation of SRCs is still poorly understood. Our hypothesis is that inhibitors of the expression and/or function of steroid receptor coactivators could overcome endocrine resistance caused by multiple upstream mechanisms, and, thus, have wide therapeutic implications in prostate and breast cancer.

To this end, recently our collaborator, Drs. Bert O'Malley and Jin Wang, made a major breakthrough in this area and successfully synthesized a novel panel of small molecule inhibitors (SMIs) of the p160 SRCs. These new panel of inhibitors have been shown to selectively reduce the levels of SRC-3 protein and potently kills breast cancer cells while not affecting normal cell viability. We are currently in the process of investigating the effectiveness of these compounds in prostate cancer.