Biomarkers or biotargets? Using competition to lure cancer cells into evolutionary traps.

Background and objectives: Cancer biomarkers provide information on the characteristics and extent of cancer progression and help inform clinical decision-making. However, they can also play functional roles in oncogenesis, from enabling metastases and inducing angiogenesis to promoting resistance to chemotherapy. The resulting evolution could bias estimates of cancer progression and lead to suboptimal treatment decisions.

Methodology: We create an evolutionary game theoretic model of cell-cell competition among cancer cells with different levels of biomarker production. We design and simulate therapies on top of this pre-existing game and examine population and biomarker dynamics.

Results: Using total biomarker as a proxy for population size generally underestimates chemotherapy efficacy and overestimates targeted therapy efficacy. If biomarker production promotes resistance and a targeted therapy against the biomarker exists, this dynamic can be used to set an evolutionary trap. After chemotherapy selects for a high biomarker-producing cancer cell population, targeted therapy could be highly effective for cancer extinction. Rather than using the most effective therapy given the cancer's current biomarker level and population size, it is more effective to 'overshoot' and utilize an evolutionary trap when the aim is extinction. Increasing cell-cell competition, as influenced by biomarker levels, can help prime and set these traps.

Conclusion and implications: Evolution of functional biomarkers amplify the limitations of using total biomarker levels as a measure of tumor size when designing therapeutic protocols. Evolutionarily enlightened therapeutic strategies may be highly effective, assuming a targeted therapy against the biomarker is available.