Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a median overall survival
limited to 1 year for advanced disease. A significant fraction of GC is due to aberrant HGF/MET axis signaling, most
commonly due to MET receptor gene amplification. However, no effective MET-targeted therapies are currently available,
with resistance frequently emerging rapidly, following an initial response. The development of additional, alternative
approaches to effectively inhibit MET and other RTKs is therefore a necessity for a cure to be found.
We recently identified a number of novel soluble decoy RTKs isoforms (sdRTKs), generated by an alternative
splicing/intronic polyadenylation (IPA) mechanism, which can act as potent natural inhibitors of RTK signaling. We
developed an antisense-based method to specifically and effectively induce IPA usage and sdRTKs expression in vitro and
in vivo. These compounds identify a new class of drugs that carry the advantage of simultaneously knocking down the
pathological targets while introducing natural dominant-negative isoforms, thus greatly increasing their efficacy.
We will apply this antisense-based approach to promote IPA and stimulate the expression of dominant-negative,
endogenous soluble decoy MET inhibitory variants (sdMET), normally expressed at low levels. sdMETs encode the
extracellular ligand-binding and dimerization domains, but lack the transmembrane and the intracellular kinase domains.
We hypothesize that sdMET-inducing compounds suppress HGF/MET signaling by a three fold-mechanism: A)
direct removal of full-length MET receptor mRNAs, B) binding and sequestration of MET ligand (HGF), and C) non-
productive hetero-dimerization with residual MET receptors. We further posit that, as the resulting products are
secreted from targeted cells, they affect signaling in both targeted and neighboring cells alike and interfere with
paracrine and autocrine loops, thus wielding an amplified effect. Since the mechanism of action is different from that of
current therapies, this strategy should be effective in all tumors that rely on HGF/MET signaling, including relapsing
ones. To this end, we will pursue the following specific aims:
1) Identification and characterization of effective inhibitory sdMET splicing variants.
2) Reprogramming of MET splicing/polyadenylation in gastric cancer cells by antisense-based splicing
redirection compounds that induce IPA.
3) Assessment of the therapeutic potential of sdMET-inducing antisense oligonucleotides in multiple gastric
cancer models, in vitro and in vivo.
These results will be important for the development of powerful novel investigative tools and therapeutic approaches in
any cancer type where the HGF/MET signaling axis plays a determinant role. The findings emerging from this study will be
broadly translatable to disease dependent on other RTKs and oncogenes, in gastric cancer and other tumors. Analogous
compounds can in fact be similarly designed to directly target other RTKs or other targets responsible for drug-resistance
and pathological signaling, or to overcome various mechanisms of resistance.