Nano- Oncologicals

Abstract

Effi cient treatment of aggressive cancers such as melanoma has been traditionally hampered by a plethora of (epi)genetic alterations that deactivate classical apoptotic death programs and potentiate multiple intrinsic mechanisms of cell survival. Targeted activation of tumor self-degradation by autophagy is emerging as an alter- native strategy to deplete tumor cells of essential organelles and promote their demise. However, autophagy is frequently activated as a fail-safe mechanism, for example, as a catabolic process to sustain the high-energy demand of tumor cells. Moreover, autolysosome formation may also be induced to counteract reactive oxy- gen or other stress-inducing signals that may accompany drug treatment. An addi- tional complication in the design of pro-autophagy treatments is that normal cells also undergo basal autophagy. Therefore, a key challenge in the fi eld is to design compounds that are selectively incorporated by malignant cells and activate self- degradation without unwanted secondary effects to normal cell compartments. Here we describe the identifi cation and functional validation of BO-110, a new double- stranded (ds)RNA-based nanocomplex that we found as a potent anti-cancer agent in vivo. BO-110 is a polyplex of viral dsRNA mimetics (improved version of the classical polyinosinic-polycytidylic acid, pIC), complexed with cationic carriers for enhanced cytosolic delivery. First tested in melanoma cells, BO-110 was found to induce a tumor-cell selective autophagosome-lysosome fusion, in part via a selective induction of the innate immunity sensor Melanoma Differentiation-Associated gene-5 (MDA5), a cytosolic dsRNA helicase. Importantly, BO-110-driven activa- tion of innate responses led to the upregulation of the pro-apoptotic protein NOXA in a manner not recapitulated by classical chemo or immunotherapeutic agents. BO-110 was also found to display a broad therapeutic effect against pancreatic can- cer, bladder cancer, and glioblastoma, among others. These results revealed a novel link between cytosolic RNA helicases, autophagy, and apoptosis that can be exploited for therapeutic intervention in otherwise highly resistant human cancers.