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Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models
James R Tonra1, Erik Corcoran, Dhanvanthri S Deevi
1ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY10014, U.S.A. James.Tonra@imclone.com
Background:
Rational strategies utilizing anticancer efficacy and biological principles are needed for the prioritization of specific combination targeted therapy approaches for clinical development, from among the many with experimental support.
Materials And Methods:
Antibodies targeting epidermal growth factor receptor (EGFR) (cetuximab), insulin-like growth factor-1 receptor (IGF-IR) (IMC-A12) or vascular endothelial growth factor receptor 2 (VEGFR2) (DC101), were dosed alone or in combination, in 11 human tumor xenograft models established in mice. Efficacy readouts included the tumor burden and incidence of metastasis, as well as tumor active hypoxia inducible factor-1 (HIF-1), human VEGF and blood vessel density.
Results:
Cetuximab and DC101 contributed potent and non-overlapping benefits to the combination approach. Moreover, DC101 prevented escape from IMC-A12 + cetuximab in a colorectal cancer model and cetuximab prevented escape from DC101 therapy in a pancreatic cancer model.
Conclusion:
Targeting VEGFR2 + EGFR was prioritized over other treatment strategies utilizing EGFR, IGF-IR and VEGFR2 antibodies. The criteria that proved to be valuable were a non-overlapping spectrum of anticancer activity and the prevention of resistance to another therapy in the combination.
Insights
Combination targeted therapy using antibodies against vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor (EGFR) showed superior anticancer efficacy and prevented treatment resistance in preclinical models.
Area of Science:
- Oncology
- Translational Research
- Cancer Therapy
Background:
- Developing rational strategies for combination targeted cancer therapy is crucial for clinical development.
- Numerous combination therapies show experimental promise, necessitating prioritization based on efficacy and biological principles.
Purpose of the Study:
- To prioritize combination targeted therapy approaches for clinical development.
- To evaluate the efficacy of antibodies targeting EGFR, IGF-IR, and VEGFR2, alone and in combination.
Main Methods:
- Tested antibodies targeting EGFR (cetuximab), IGF-IR (IMC-A12), and VEGFR2 (DC101) in 11 human tumor xenograft models.
- Assessed tumor burden, metastasis, tumor hypoxia-inducible factor-1 (HIF-1), human VEGF, and blood vessel density.
Main Results:
- Cetuximab (EGFR) and DC101 (VEGFR2) provided potent, non-overlapping benefits in combination.
- DC101 prevented resistance to IMC-A12 + cetuximab in colorectal cancer.
- Cetuximab prevented resistance to DC101 in pancreatic cancer.
Conclusions:
- Combination therapy targeting VEGFR2 and EGFR was prioritized over other combinations involving IGF-IR.
- Non-overlapping anticancer activity and prevention of treatment resistance were key prioritization criteria.
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