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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide
David S Hong1, Razelle Kurzrock, Yun Oh
1Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. dshong@mdanderson.org
Purpose:
The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors.
Experimental Design:
A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein.
Results:
Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck).
Conclusions:
LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.
Insights
The antisense oligonucleotide LY2275796, targeting eukaryotic initiation factor 4E (eIF-4E), was well tolerated up to 1,000 mg in advanced cancer patients. While it reduced tumor eIF-4E expression, further studies are needed to assess its efficacy in combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Eukaryotic initiation factor 4E (eIF-4E) is a key mRNA translation regulator often upregulated in various tumors.
- Antisense oligonucleotides offer a targeted approach to modulate gene expression in cancer therapy.
Purpose of the Study:
- To determine the maximum-tolerated dose (MTD) of the novel antisense oligonucleotide LY2275796 in patients with advanced solid tumors.
- To assess the pharmacokinetic profile and target engagement (eIF-4E downregulation) of LY2275796.
Main Methods:
- Phase I clinical trial involving dose escalation of LY2275796 in patients with advanced malignancies.
- Pharmacokinetic sampling and tumor biopsy analysis to quantify LY2275796 levels and eIF-4E expression (mRNA and protein).
Main Results:
- The MTD of LY2275796 was established at 1,000 mg weekly, with dose-limiting toxicity observed at 1,200 mg.
- LY2275796 administration led to decreased eIF-4E expression in tumor biopsies across most patients.
- The drug was generally well-tolerated, with most toxicities being grade 1-2. Seven patients achieved stable disease.
Conclusions:
- LY2275796 demonstrates acceptable safety and tolerability up to 1,000 mg in advanced cancer patients.
- Pharmacodynamic effects (eIF-4E downregulation) were observed, but direct anti-tumor responses were limited as a monotherapy.
- Further investigation of LY2275796 in combination with other anti-cancer agents is warranted.
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