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

A G Duffy, O V Makarova-Rusher, S V Ulahannan, O E Rahma, S Fioravanti, M Walker, S Abdullah, M Raffeld, V Anderson, N Abi-Jaoudeh, E Levy, B J Wood, S Lee, Y Tomita, J B Trepel, S M Steinberg, A S Revenko, A R MacLeod, C J Peer, W D Figg, T F Greten, A G Duffy, O V Makarova-Rusher, S V Ulahannan, O E Rahma, S Fioravanti, M Walker, S Abdullah, M Raffeld, V Anderson, N Abi-Jaoudeh, E Levy, B J Wood, S Lee, Y Tomita, J B Trepel, S M Steinberg, A S Revenko, A R MacLeod, C J Peer, W D Figg, T F Greten

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 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. 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 seven of 15 (47%) patients who were progressing before 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 posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Keywords: antisense; colorectal cancer; eIF4E.

Conflict of interest statement

Conflict of interest: Revenko and MacLeod are employers and shareholders of Isis Pharmaceuticals, Inc.

© 2016 UICC.

Figures

Figure 1.
Figure 1.
EIF4e ASOs reduce expression of EIF4e mRNA. (a) COLO-201 and HCT-116 cells were transfected with 25 or 50 nM of control or EIF4e ASO. Forty-eight hours after transfection cells were collected for EIF4e RNA quantification by qPCR. (b) Cells were also harvested every 2 days for direct cell enumeration.
Figure 2.
Figure 2.
EIF4e ASOs inhibit proliferation of colorectal carcinoma cells and have at least additive antiproliferative effects with irinotecan and SN-38. COLO-201 (a) or HCT-116 (b) cells were transfected with 25 or 50 nM of control or EIF4e ASO for 48 hr and treated with irinotecan (upper panels) or SN-38 (lower panels) for another 72 hr. Cell proliferation was quantified by Crystal Violet staining. Proliferation was normalized to untreated cells (a and b, left panels) or to the ASO-transfected irinotecan untreated (a and b, upper right panels) and SN-38 untreated (a and b, lower right panels) cells.
Figure 3.
Figure 3.
(a) Waterfall plot showing magnitude of objective responses in evaluable patients; (b) Kaplan–Meier curve for progression-free survival.
Figure 4.
Figure 4.
eIF4E mRNA in (a) peripheral blood (n=19) and (b) paired pre- and posttreatment tumor biopsies (n=9).

Source: PubMed

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