Oncogenic transcription factors are important mediators of process involved in cell growth, differentiation, and de-differentiation, and they play important roles in oncogenesis, cancer progression, and metastasis.
For instance, the forkhead box (Fox) family of transcription factors plays important roles in regulating cellular proliferation, differentiation, longevity, and cellular transformation. Wang et al., Proc. Natl. Acad. Sci. USA 98:11468-11473 (2001). The mammalian transcription factor Forkhead Box M1 (FoxM1; previously known as HFH-11B, Trident, WIN, or MPP2) is induced during the G1 phase of the cell cycle, and its expression continues through the S phase and mitosis (1). FoxM1 is especially important for the execution of the mitotic program as seen by the failure of FoxM1-depleted cells to progress beyond the prophase stage of mitosis (2). This is consistent with the demonstration that FoxM1 transcriptionally upregulates a number of target genes including Cyclin B, Survivin, Aurora B kinase, Cdc25b phosphatase, and Plk1, all of which are implicated in mitosis (2, 3). Also, FoxM1 transcriptionally induces Skp2 and Cks1 (specificity subunits of Skp1-Cullin1-F-box ubiquitin ligase complex) leading to the degradation of cyclin-dependent kinase inhibitors p21WAF1 and p27KIP1, thereby resulting in cell cycle progression (2). In line with its pro-proliferative nature, while FoxM1 is expressed in all dividing mammalian cells and tumor-derived cells, its expression is turned off in terminally differentiated cells (4-7).
FoxM1 is overexpressed significantly in primary breast tumors (8), basal cell carcinomas (9), hepatocellular carcinomas (10, 11), intrahepatic cholangiocarcinomas (12), non-small cell lung cancers (13), anaplastic astrocytomas, and glioblastomas (14). Also, increased levels of FoxM1 has been seen to accelerate prostate cancer development and progression in mouse models (15). Furthermore, a large-scale analysis of microarray results revealed that FoxM1 is one of the most common genes overexpressed in a majority of solid tumors (16). Together, these studies indicate that FoxM1 could be an attractive target for anti-cancer therapy. This notion is supported by a recent finding that depletion of FoxM1 by RNA interference (RNAi) in breast cancer cells leads to mitotic catastrophe (8). In a similar manner, knock-down of FoxM1 by small interfering RNAs (siRNAs) in several prostate and lung cancer cell lines was shown to lead to a significant reduction in cell proliferation and anchorage-independent cell growth on soft agar (13, 15). Consistent with these observations, inhibition of FoxM1 transcriptional activity by a peptide containing amino acids 24-46 of p19ARF also reduced anchorage independent cell growth (17).
The central role of oncogenic transcription factors, such as FoxM1, in regulating cell growth, proliferation, and differentiation, and in pathologies associated with changes in their functioning, such as cancers, makes them attractive targets for drug development. Accordingly, there has been a great deal of research and development work not only on characterizing these factors and their roles in cellular and disease processes, but also on therapeutic agents that modulate their activity. Although these efforts have resulted in some success, the agents that have been developed thus far are far from ideal. There is a need therefore for improved methods of identifying agents that modulate the activity of oncogenic transcription factors, and for the agents themselves, as well as for formulations comprising the agents and for methods of using the agents and composition to treat diseases, such as malignancies and cancers.