Abstract SY15-03: Drugging “undruggable” transcription factor drivers in cancer

Abstract

Abstract Dysregulation of gene expression is a hallmark of all cancers. It is critical for conferring stem cell like properties, such as self-renewal and chemo-resistance, on these cancer cells. Such properties contribute to the inability to completely eradicate cancer cells, thereby leading to relapse. The specific gene expression program that confers these properties derives from aberrant activity of specific transcription factors which are drivers of disease. There are numerous examples of such transcription factor drivers in cancer (ERG in prostate cancer, ETV1 in prostate cancer and GIST, RUNX1-ETO and CBFβ-SMMHC in acute myeloid leukemia, etc.). Clearly, the most direct and effective approach to alter this gene expression program is to target the activity of these transcription factors which are drivers of disease. While the paradigm is shifting significantly, transcription factors have traditionally been viewed as “undruggable”. This results from the challenges associated with targeting either the protein-DNA or protein-protein interactions that typically mediate their function. Recent successes in this area are clearly breaking down this paradigm. Targeting of transcription factors is a very different approach to current approaches to targeted therapy which have heavily focused on kinase inhibitors. Targeting transcription factor drivers will likely alter the stem cell like properties of the cancer cell such as self-renewal, the DNA repair alterations which lead to enhanced rates of mutagenesis, and the chemo-resistance which limits effectiveness of chemotherapy drugs. It is also likely that agents targeting transcription factors will show synergy with appropriately targeted kinase inhibitors. We have developed a specific, potent, and effective protein-protein interaction inhibitor for the CBFβ-SMMHC fusion protein which is a driver in inv(16) acute myeloid leukemia (Illendula et al. Science 347: 779-784 (2015)). The efficacy of this inhibitor of a critical protein-protein interaction of the CBFβ-SMMHC transcription factor fusion protein clearly demonstrates the utility of directly targeting transcription factor drivers in cancer. Based on this success, we are targeting other transcription factor drivers in leukemia as well as in other cancers. Two examples of our efforts in this area will be presented. Citation Format: John Bushweller. Drugging “undruggable” transcription factor drivers in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY15-03.