The tale of the targeted mouse
By Sarah Glass
Researchers from the labs of Robert Coffey (Medicine) and Jacob Houghton (Radiology and Radiological Sciences) report in Gastroenterology the identification of two human antibodies, P1X and P2X, that can neutralize EGFR in mice. EGFR, or epidermal growth factor receptor, contributes to cancer progression by increasing the signaling of pathways related to cell proliferation, invasion, and survival. Antibodies that neutralize or disable human EGFR, like cetuximab, have therapeutic utility and are FDA approved for the treatment of several cancers such as colorectal cancer (CRC). Until now, there were no known antibodies that targeted mouse EGFR, which limited the kinds of pre-clinical research that scientists could carry out.
Studies leading up to cetuximab’s approval involved mice injected with human EGFR-expressing tumors but did not include models where tumors developed naturally in the mice without injection, as antibodies that block mouse EGFR did not exist at the time so there would be no good way to target those tumors. This was of grave concern given that mouse models are essential in determining unexpected toxicities without putting cancer patients at risk. Mouse models where EGFR is neutralized with antibodies could also be used to determine the viability of new drug combinations that are currently not approved for treating patients. The discovery of a mouse antibody that targets EGFR will inform and refine the best practice for colon cancer care in the clinic.
Resistance to antibody treatments occurs when a mutation in a patient’s EGFR changes the overall shape of the receptor so that the drug can no longer bind. An antibody cocktail called MM-151 can overcome cetuximab resistance in CRC patients by binding to different portions of human EGFR, such that the patient cannot accumulate enough simultaneous mutations to render all three of its antibodies ineffective. P1X and P2X are two of those antibodies, and until this study, no group had shown that they could also be used in mice.
Using a unique mouse strain that glows emerald green where EGFR is present, first author Won Jae Huh and colleagues showed that P1X and P2X work together to stop the growth of colonic tumoroids (cancerous micro-organs) and block EGFR signaling in intestinal tumoroids. They found that the two antibodies not only bound to the emerald EGFR, but also reduced the overall levels of fluorescence, meaning that the drug cocktail led to the breakdown of the receptor. Losing EGFR made the cancer cells more sensitive to elimination: incredibly, treatment with P1X and P2X for just two weeks reversed cancer-like histological features in a mouse model of Ménétrier’s disease, an EGFR-driven premalignant stomach disorder.
With this work, the group became the first to demonstrate the neutralization of EGFR with antibodies in mice. This breakthrough will allow researchers and physicians to study EGFR-targeting drugs in mice, helping them discover new combination therapies or avoid potential pitfalls in their quest to improve the outcomes of patients with EGFR-driven disorders.
Funding was provided by the National Cancer Institute, the American Gastroenterological Association, and Vanderbilt University.