Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750 – an antisense oligonucleotide against eIF4E – in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer

Abstract

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160mg/m²-biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control of 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in 7/15 (47%) patients who were progressing prior to study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and post-therapy tumor biopsies penetration of the ASO into the site of metastasis. This article is protected by copyright. All rights reserved.

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