Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors

Chemically synthesized, small interfering RNAs (siRNA) are currently used as a new class of therapeutic molecules, allowing the controlled down-regulation of pathologically relevant gene expression e.g., oncogenes and other similar targets in cancer 1, 2, 3.However, the overall negative charge of siRNA molecules (up to 40 negative charg-es) and the relatively high molecular weight (12,000 – 14,000 Da) prevent the functional uptake of these novel therapeutic molecules in vivo. Besides the inefficient uptake and the degradation in endosomal compartments at the cellular level, non-formulated siRNAs are rapidly cleared by renal excretion from the blood stream when administered i.v. 4.To overcome these limitations, a variety of non-viral nanoparticles (50 – 200 nm) have been recently developed enabling chemically synthesized siRNA to be used therapeuti-cally for inhibition of RNAi-mediated tumor growth. Atu027 is a novel RNAi therapeutic agent based on cationic lipoplexes containing chemically stabilized siRNAs, which target Protein Kinase N3 (PKN3) gene expression in the vascular endothelium (Figure 1) 5. PKN3, a member of the AGC kinase fam-ily, has been identified as a promising, novel therapeutic target in cancer cells for inhibiting tumor progression and lymph node metasta-sis formation 6. These studies have revealed that PKN3 mediates malignant cell growth downstream of the chronically activated phosphoinositide 3-kinase (PI3K) pathway 6. Recently, PKN3 has also been considered as a suitable therapeutic target for modulating tumor-associated angiogenesis. Preclinical data, obtained in various cancer mouse mod-els, revealed target-specific, RNAi-mediated silencing of PKN3 expression and significant inhibition of tumor progression and metasta-sis formation [