Splice modulating oligomers as cancer therapeutics.

Genes are transcribed to produce pre-mRNAs, which are then spliced to create the mature mRNAs translated into protein. In recent years, improved deep sequencing technologies have shown greater than 90% of human pre-mRNAs undergo alternative splicing, thereby amplifying the potential protein products from each gene [1]. Alternatively spliced forms of pre-mRNA may code for proteins with related, distinct, or even opposing functions [1]. Many growth factor and hormone receptors and signaling molecules implicated in cancer have natural splice variants, some of which have been shown to act as dominant negatives. We hypothesized that by altering splicing to decrease growth-promoting and/or increase expression of dominant negative varieties we could eliminate abnormal dependence on growth factors, decrease metastatic potential, and promote cancer cell death. By binding to specific intronic or exonic regions or intron-exon junctions, splice modulating oligomers, which are cDNA sequences, can alter the outcome of splicing [e.g., 2, 3]. To our knowledge, no one had previously tapped the potential of splice modulating oligomers to increase the relative activity of natural dominant negatives in order to combat disease. Where splice modulating oligomers had begun to be explored as therapeutics was for diseases that result from splicing errors and the production of a non-functional protein [4, 5]. Dominant negative receptors may inhibit signaling from the growth-promoting form of the receptor in a variety of ways. In the simplest situation, a dominant negative receptor binds ligand and therefore reduces availability to the growth-promoting receptor. In other instances, the dominant negative receptor may generate an alternate intracellular signal [e.g., 6–9]. Such amplification of the effect of dominant negative receptors through a signaling cascade makes an increase in their relative expression all the more effective. Importantly and additionally, the signals generated can promote differentiation and/or apoptotic cell death [6–8], thereby Editorial