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Cancer Prevention Strategies That Address the Evolutionary Dynamics of Neoplastic Cells: Simulating Benign Cell Boosters and Selection for Chemosensitivity

Divisions of ¹ Human Biology and ² Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Departments of ³ Medicine and ⁴ Genome Sciences, University of Washington, Seattle, Washington; and ⁵ Department of Computer Science, University of New Mexico, Albuquerque, New Mexico

Requests for reprints: Carlo C. Maley, Division of Human Biology, Fred Hutchinson Cancer Research Center, P.O. Box 19024, Mailstop C1-157, Seattle, WA 98109. Phone: 206-355-7425; Fax: 206-667-6132. E-mail: cmaley{at}alum.mit.edu

Cells in neoplasms evolve by natural selection. Traditional cytotoxic chemotherapies add further selection pressure to the evolution of neoplastic cells, thereby selecting for cells resistant to the therapies. An alternative proposal is a benign cell booster. Rather than trying to kill the highly dysplastic or malignant cells directly, a benign cell booster increases the fitness of the more benign cells, which may be either normal or benign clones, so that they may outcompete more advanced or malignant cells in a neoplasm. In silico simulations of benign cell boosters in neoplasms with evolving clones show benign cell boosters to be effective at destroying advanced or malignant cells and preventing relapse even when applied late in progression. These results are conditional on the benign cell boosters giving a competitive advantage to the benign cells in the neoplasm. Furthermore, the benign cell boosters must be applied over a long period of time in order for the benign cells to drive the dysplastic cells to extinction or near extinction. Most importantly, benign cell boosters based on this strategy must target a characteristic of the benign cells that is causally related to the benign state to avoid relapse. Another promising strategy is to boost cells that are sensitive to a cytotoxin, thereby selecting for chemosensitive cells, and then apply the toxin. Effective therapeutic and prevention strategies will have to alter the competitive dynamics of a neoplasm to counter progression toward invasion, metastasis, and death.

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