An unusual approach confirms a suspected synergy between two promising colon cancer treatments

Colon cancer, especially in a metastatic setting, remains a leading cause of cancer-related death worldwide. The heterogeneity of colon tumors is a major factor in treatment failures, as these tumors can exhibit a host of genetic makeups and histological features that prohibit a one-size-fits-all approach.

Predicting the efficacy of a given treatment is a highly desirable strategy when an individual patient’s tumor has been genetically characterized. Consequently, scientists developing novel treatments need a robust way to test their hypotheses in a test system that is as close to an actual patient as possible. Patient derived xenograft (PDX) models, where patient tumors are established as models in immunodeficient mice, fit the bill in terms of reflecting the variety of patient tumors. Unfortunately, such studies quickly become extremely expensive when applied to a large population of tumors.

Scientists at Eli Lilly & Co. employed an unusual approach to confirm a suspected synergy between two treatments. In a study run at Charles River Freiburg and another contract research organization, they investigated a total of 79 colon cancer PDX models in a setup that used a single mouse per treatment arm, rather than the more conventional approach where group size ranges from 6-10 animals.

This radically different study design requires a different way of looking at experimental results. Treatment efficacy is evaluated across the panel of tumor models, while the results from individual models lose a bit of statistical weight. The robustness of the study design results from a yes/no answer on the efficacy of a compound (or a combination treatment), which tells you that the format is best suited for highly active compounds, rather than subtle modulators of anticancer responses. If you predicted the response beforehand based on genetic analyses, you can then compare the results to your prediction data to confirm the experimental hypothesis. Set up in this way, this “single mouse trial” reduces the number of animals needed to obtain a meaningful result, a big plus for those of us committed to the spirit of the “Three Rs” tenet- Replacement, Reduction and Refinement.

Lilly scientists tested cetuximab (the EGFR inhibitor approved as Erbitux®) in combination with LSN3074753 (a close analogue of their investigative pan-RAF inhibitor LY3009120). These treatments work through inhibition of specific targets within the MAPK and EGFR pathways which play important roles in controlling cell growth. The compounds were investigated in a panel of colon cancer PDX models of different BRAF and KRAS mutation status. Mutations in these two genes are a major factor in the resistance of colon cancer to treatment with cetuximab and another EGFR inhibitor, panitumumab. Cetuximab results mimicked those encountered in patients, and the PDX trial confirmed that the presence of these mutations correctly predicted a synergistic efficacy between cetuximab and LSN3074753; the combination approach was significantly more effective than either agent alone.

The results of this trial, published here, confirm the combined inhibition of MAPK and EGFR pathways as a potentially viable treatment option for metastatic colon cancer, as many MAPK pathway inhibitors are currently in clinical trials.