title: 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 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.
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: A G
authors.initials: AG
authors.lastname: Duffy
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: O V
authors.initials: OV
authors.lastname: Makarova-Rusher
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: S V
authors.initials: SV
authors.lastname: Ulahannan
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: O E
authors.initials: OE
authors.lastname: Rahma
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: S
authors.initials: S
authors.lastname: Fioravanti
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: S
authors.initials: S
authors.lastname: Abdullah
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: M
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: V
authors.initials: V
authors.lastname: Anderson
authors.affiliation: Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: N
authors.initials: N
authors.lastname: Abi-Jaoudeh
authors.affiliation: Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: E
authors.initials: E
authors.lastname: Levy
authors.affiliation: Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: B J
authors.initials: BJ
authors.lastname: Wood
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Y
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: J B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: A S
authors.initials: AS
authors.lastname: Revenko
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: A R
authors.initials: AR
authors.lastname: MacLeod
authors.affiliation: Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: C J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: T F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D000328:Adult; D000368:Aged; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D009843:Oligoribonucleotides / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C569652:LY 2275796; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; D012333:RNA, Messenger; D000077146:Irinotecan; D002166:Camptothecin
keywords: antisense; colorectal cancer; eIF4E