| dc.description.abstract | Triple negative breast cancer (TNBC) is a highly aggressive BC subtype with limited molecularly targeted therapies. Aberrant activation of the phosphatidylinositol 3-kinase/ mammalian target of rapamycin (PI3K/mTOR) pathway is often seen in TNBC but attempts to target this pathway have been altogether ineffective for TNBC patients. Less is known regarding the signaling complex mTOR complex 2 (mTORC2) which is a central integrative node of the PI3K/mTOR pathway and regulates pro-oncogenic activities such as tumor cell survival, motility/metastasis, and chemoresistance. However, small molecule inhibitors that potently and selectively block mTORC2 do not exist. Here, we leverage short interfering RNA (siRNA) technology to block expression of Rictor, an mTORC2-required cofactor, to test the therapeutic utility of mTORC2 signaling inhibition in TNBC.
siRNA therapies are a promising strategy for treating diseases that lack druggable targets, but their systemic delivery is limited by rapid kidney clearance, low cellular uptake, and poor endosome disruption. siRNA-carrying nanoparticles (si-NPs) can improve siRNA delivery to target organs but continue to face delivery challenges such as limited stability, off-target toxicities, and suboptimal tumor accumulation. Ternary si-NPs containing siRNA, an NP core-forming polymer, and an NP surface-forming polymer have the potential to improve tumor silencing activity because of the participation of both polymers in siRNA encapsulation and pH-responsive endosome disruptive activity. Through concomitant structure-function optimization of the core-forming polymer ratio and molecular weight, we identified a lead ternary si-NP with enhanced stability, potent tumor gene silencing activity, and minimal toxicity.
To enable therapeutic Rictor knockdown in TNBCs in vivo, we utilized our optimized si-NP for intravenous delivery of siRictor, resulting in robust tumor siRNA accumulation, Rictor knockdown, and mTORC2 inhibition. Selective mTORC2 inhibition using siRictor in vivo decreased tumor cell proliferation, survival, and tumor growth in TNBC tumor-bearing mice, and increased paclitaxel-induced tumor growth inhibition. Together, this work supports Rictor ablation as an effective approach for therapeutic mTORC2-selective blockade and identifies a novel RNAi nanotechnology for treatment of PI3K-active TNBC. | |
