Development of a Novel Class of Self-Assembling dsRNA Cancer Therapeutics: a Proof of Concept Investigation

Abstract

22Cancer has proven to be an extremely difficult challenge to treat. Several 23 fundamental issues currently underlie cancer treatment including differentiating 24 self from non-self, functional coupling of the recognition and therapeutic 25 components of various therapies, and the propensity of cancerous cells to develop 26 resistance to common treatment modalities via evolutionary pressure. Given these 27 limitations, there is an increasing need to develop an all-encompassing therapeutic 28 that can uniquely target malignant cells, decouple recognition from treatment, and 29 overcome evolutionarily driven cancer resistance. We describe herein, a new class 30 of programmable self-assembling dsRNA-based cancer therapeutics, that uniquely 31 targets aberrant genetic sequences, and in a functionally decoupled manner, 32 undergoes oncogenic RNA activated displacement (ORAD), initiating a therapeutic 33 cascade that induces apoptosis and immune activation. As a proof-of-concept, we 34show that RNA strands targeting the EWS/Fli1 fusion gene in Ewing Sarcoma cells 35 that are end-blocked with phosphorothioate bonds and additionally sealed with a 36 2'-U modified DNA protector can be used to induce specific and potent killing of cells 37 containing the target oncogenic sequence, but not wildtype. 38 39 40 41 42