Editors' ChoiceCancer

Running Interference on Tumor Growth

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Science Translational Medicine  13 Feb 2013:
Vol. 5, Issue 172, pp. 172ec29
DOI: 10.1126/scitranslmed.3005831

Small interfering RNAs (siRNAs), as the name suggests, provide cells with a critical method of regulating gene expression by targeting specific transcripts for destruction. For years, scientists have had success with altering cellular processes by introducing laboratory-generated siRNA molecules into cells. However, translating these approaches into clinical practice has remained elusive. One of the challenges has been selectively delivering siRNA molecules to tumor tissue while sparing normal cells.

Tabernero and colleagues attempted to tackle this challenge by using lipid nanoparticles, coined “ALP-VSP,” that contain two different siRNAs targeting genes known to be important in many types of cancer: vascular endothelial growth factor-A (VEGF-A) and kinesin spindle protein (KSP). They tested ALP-VSP in a phase I clinical trial of 41 patients with advanced cancer that had spread to the liver, many of whom had failed multiple previous therapies. The drug was administered intravenously and well tolerated in nearly all patients. By examining tumor biopsies before and after treatment, the authors were able to demonstrate uptake and activity within tumor cells. Nearly half of the subjects demonstrated by means of magnetic resonance imaging a decrease in tumor blood flow, which is a common finding in therapies that effectively target tumor vasculature. Despite being a phase I study, there were promising signs of efficacy. Three patients experienced no appreciable growth of their tumors for up to 18 months using conventional imaging techniques. One patient with metastatic endometrial cancer demonstrated a complete response, with disappearance of all lesions on a computed tomography scan.

This study demonstrates the promise held by siRNA-based cancer therapies and opens up new therapeutics strategies within oncology and potentially other disorders. But although the new results are encouraging, larger prospective trials will be needed to definitively demonstrate the safety and utility of these approaches.

J. Tabernero et al., First-in-man trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liveri. Cancer Discov., published online 28 January 2013 (10.1158/2159-8290.CD-12-0429). [Abstract]

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