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Updated: May 31, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Estimating preclinical efficacy targets utilizing cetuximab efficacy in KRAS mutant and wild-type colorectal cancer
Marie Prewett1, Rajiv Bassi, Keren Paz
1ImClone Systems, Eli Lilly and Company, Department of Preclinical Pharmacology, Alexandria Center for Science and Technology, 450 First Avenue, New York, NY 10016, USA. marie.prewett@imclone.com
Background:
Clinically relevant targets for developmental drug efficacy in animal models of cancer are critical yet understudied parameters.
Materials And Methods:
Cetuximab, a chimeric antibody to epidermal growth factor receptor (EGFR), was administered to athymic mice bearing subcutaneous tumors established with 13 human colorectal cancer cell lines of varying biomarker status, defined by DNA sequencing and RT-PCR.
Results:
If tumor growth inhibition is taken as a target, as is commonly done, then in contrast to the clinical situation where KRAS mutation strongly predicts for a lack of clinically meaningful benefit in colorectal cancer patients, cetuximab alone and in combination with irinotecan-based chemotherapy were efficacious in a similar proportion of KRAS wild-type and mutant models. It was only when tumor regression was utilized to define relevant efficacy that cetuximab monotherapy was efficacious in KRAS wild-type, but not mutant models. Adding cytotoxic therapy to cetuximab treatment increased tumor regression frequency in both genotypes to the point that once again the response was similar for KRAS wild-type and mutant models.
Conclusion:
Our data support shifting the threshold for claiming clinically relevant targeted therapy efficacy in subcutaneous xenograft models towards tumor regression, rather than tumor growth inhibition, focusing on the evaluation of tumor cells that are addicted to the pathways being targeted.
Insights
Evaluating targeted therapy efficacy requires focusing on tumor regression, not just growth inhibition. This approach better identifies effective cancer treatments, especially for colorectal cancer, regardless of KRAS mutation status.
Area of Science:
- Oncology
- Pharmacology
- Translational Research
Background:
- Defining clinically relevant efficacy targets in preclinical cancer models is crucial but underexplored.
- Current models often use tumor growth inhibition, which may not accurately reflect clinical outcomes for targeted therapies.
Purpose of the Study:
- To evaluate the efficacy of cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, in preclinical colorectal cancer models.
- To determine if tumor regression, rather than tumor growth inhibition, is a more relevant endpoint for predicting targeted therapy efficacy.
Main Methods:
- Administered cetuximab to athymic mice with human colorectal cancer xenografts.
- Characterized tumor biomarker status (KRAS mutation) using DNA sequencing and RT-PCR.
- Assessed efficacy based on tumor growth inhibition and tumor regression.
Main Results:
- Cetuximab efficacy, based on tumor growth inhibition, was similar in KRAS wild-type and mutant models.
- Tumor regression was observed with cetuximab monotherapy only in KRAS wild-type models.
- Combination therapy with cetuximab and chemotherapy improved regression in both KRAS genotypes.
Conclusions:
- Tumor regression is a more sensitive endpoint than tumor growth inhibition for assessing targeted therapy efficacy in preclinical models.
- This shift in evaluation criteria may better identify drugs effective against tumors dependent on targeted pathways.
- Findings suggest re-evaluating preclinical models to better align with clinical responses in colorectal cancer treatment.
