STAT3 is a transcription factor that has been shown to play a key and necessary role in the development of several cancers. In particular, 30%-60% of breast cancer samples show the improper constitutive activation of STAT3, and STAT3 has been established as a desirable target for cancer therapy. Many genes that are involved in oncogenesis can express antagonistic pro-tumorigenic and anti-tumorigenic isoforms through a process known as alternative splicing, and this is true for STAT3 as well. By alternative splicing, STAT3 can generate an anti-oncogenic variant called STAT3-beta, which has the potential to block the tumorigenic activity of the active STAT3-alpha isoform. Current anti-STAT3 approaches are aimed at eliminating or blocking STAT3 activity. If the treatment is not completely effective, residual STAT3 might still show oncogenic activities, and compensatory mechanisms typically intervene to increase transcription of knocked-down genes, thus tending to reinstate some functions, which could be deleterious.
Re-direction of splicing toward a dominant negative variant present the distinctive advantage that the oncogenic isoform is eliminated while, at the same time, an equal amount of a beneficial variant is introduced. In addition, feedback mechanisms that act by activating transcription are less likely to be activated (because there is no net loss of RNA or protein), and if they do, the anti-oncogenic variant will be prevalently induced. Because splicing re-direction acts upon pre-existing endogenous levels of RNA, it is maximally efficacious where the target oncogene is expressed at the highest levels (i.e., cancer cells), whereas it will have no effect if no or little oncogene is expressed (i.e., normal cells), thus introducing an intrinsic level of specificity for cancer cells.
This study is the continuation of a previous Department of Defense-funded work where we showed that indeed antisense-based compounds can be developed to re-direct STAT3 splicing toward its dominant-negative variant and that this switch is associated with cancer cell death and tumor regression in a murine breast cancer mouse model. We propose now to expand these studies to develop a next generation of compounds to move this promising approach from proof of principle to the preclinical studies phase.