Abstract
The RNAi therapeutic Atu027 is well tolerated and active in patients with advanced solid tumors.
Major finding: The RNAi therapeutic Atu027 is well tolerated and active in patients with advanced solid tumors.
Concept: Atu027-mediated silencing of protein kinase N3 in endothelial cells may promote vessel normalization.
Impact: Treatment with Atu027 may prevent and target metastatic lesions in various advanced cancers.
Administration of siRNA molecules enables targeted downregulation of specific genes and is being developed as a potential antitumor therapeutic strategy. Atu027 is a liposomal RNAi therapeutic agent containing siRNA directed against protein kinase N3 (PKN3), a downstream effector of the PI3K pathway that promotes tumor cell growth and angiogenesis. Preclinical studies have shown that Atu027 silences PKN3 expression in vascular endothelial cells and inhibits invasive tumor growth and metastasis in mice, and mechanistic studies suggest that Atu027 may prevent metastatic spread by enhancing vessel integrity and reducing vascular permeability. Schultheis and colleagues investigated the safety and efficacy of escalating doses of Atu027 in a first-in-human phase I study in 34 patients with advanced refractory solid tumors. Atu027 was well tolerated at all doses and a maximum tolerated dose was not reached. The majority of adverse events were grade 1 or 2, with the most frequent treatment-related adverse event being fatigue, and only one dose-limiting toxicity was observed at the highest dose. Moreover, in contrast to other liposomal RNAi therapies, administration of Atu027 did not significantly activate innate immune responses and did not require immunosuppressive premedication. Atu027 treatment resulted in disease stabilization in 41% of patients, including 8 patients who exhibited stable disease at the end of the study and 7 patients who experienced partial or complete regressions of distant metastatic lesions. Although biopsies were not obtained as part of this trial, analysis of serum plasma proteins following treatment revealed decreased plasma concentrations of the soluble variant of VEGF receptor 1 (sVEGFR1, also known as sFLT1) in 12 of 20 patients, suggesting that sVEGFR1 may represent a potential serum biomarker of vascular response to Atu027. These results indicate that Atu027 is safe and effective in various advanced cancers and support additional clinical trials of Atu027 in combination with cytotoxic drugs.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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