Triple-negative breast cancers (TNBC) lack the molecules on their cell surface that are used in targeted therapies of other breast cancers. This makes them difficult to treat, leading to poorer outcomes for patients. An alternative target could be the epidermal growth factor receptor (EGFR), which is present in greater numbers on the surface of many TNBC. As it is also present on healthy cells, targeting this molecule could lead to toxicity. In this study, an antibody is used that can specifically recognize the EGFR on cancer cells. Binding it to a bacterial toxin creates a potential targeted therapy for TNBC.
The treatment of TNBC is a challenge. The lack of estrogen receptor, progesteron receptor or HER2 on the cell surface prevent the use of established targeting therapies. Treatment thus relies on conventional chemotherapies, which ofter result in drug-resistant relapse. The need to create a targeted strategy for TNBC as well is very high.
EGFR is present in greater numbers on most TNBC cells, offering a potential target. However, targeted therapies are hampered by the presence of EGFR on healthy cells as well. Antibodies could provide a solution. These are proteins created by the cells of the immune system to specifically recognize and label intruders for destruction. Indeed, such an antibody, called m806, was discovered that recognizes a region of EGFR that is only exposed under oncogenic conditions. It didn’t bind to healthy cells and showed no toxicity in previous phase I clinical trials.
In this study, a fragment of the antibody that is responsible for the recognition is coupled to a bacterial toxin. The resulting “immunotoxin” is capable of causing cell death.
The nuts and bolts
In intial experiments, the selectivity of the immunotoxin for TNBC cell lines with aberrant EGFR was confirmed . It was also shown to successfully kill cells, with an increased potency at higher concentrations. TNBC cells without aberrant EGFR on the surface showed no loss in viability, but were sensitive to the toxin when another antibody that targets normal EGFR was used.
Targeting tumors in the body is a lot more complex than in individual cells grown in the lab. Therefore, the immunotoxin’s effects were also determined in mice, implanted with a TNBC tumor. Only the active immunotoxin succeeded in slowing down tumor growth and creating lesions of dead cancer cells. Furthermore, the treatment was well tolerated and resulted in little to no weight loss.
How will this help me?
This study showed that by combining fragments from a bacterial toxin and an antibody specific to cancer EGFR could slow down tumor growth without side effects in mice. Full remission was not observed at the current dosage, but further research will build on these early stage results to optimize the dose before starting clinical trials. The concept shows potential to tackle other EGFR overexpressing cancers as well, such as glioblastoma or non-small cell lung cancer.
Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer – JNCI Journal of the National Cancer Institute (2016).