Cancer Chemotherapy Informed by Evolutionary Considerations

I recently had the opportunity to learn first-hand about the research of Robert Gatenby.  Dr. Gatenby is a radiologist, but he is probably not your typical radiologist.  He has been employing mathematical methods and the principles and concepts of evolutionary biology in an effort improve therapy for cancers that have historically been relatively unresponsive to traditional approaches based on highly toxic chemotherapeutic agents. 

My introduction to his work was an absorbing commentary on this topic in Nature (2009).  In this piece, Gatenby suggested provocatively, that aiming for the maximum extent of tumor cell destruction might result in a sort of pyrrhic victory.  His reasoning is that by exerting maximum selection pressure on the tumor cell population the likely result would be the preferential proliferation of cells that possessed high levels of resistance to the chemotherapeutic agents being used but that were less fit (in the absence of therapeutic agents) than the chemosensitive cells, thereby setting the stage for an extremely difficult-to-treat relapse. 

Alternatively, therapy could be aimed at limiting the proliferation of the tumor cells to tolerable levels without seeking complete annihilation of the malignant population.  In that case, the goal would be to create a manangeable steady-state that transforms the cancer into a chronic disease.  As motivation for his approach to cancers that involve widespread cellular dissemination and extensive cellular and microenvironmental heterogeneity in relevant characteristics, Gatenby references ecological examples relating to several invasive species and the largely fruitless attempts to eradicate them completely.  Mathematical modeling of tumor cell dynamics supports the notion that host survival can be maximized by using a “treatment-for-stability strategy” instead of a “treatment-for-cure strategy” (Gatenby et al., 2009).  Experimental results with a model system in which an ovarian cancer cell line (OVCAR-3) is introduced into immunodeficient mice also support the principle underlying of this approach (Gatenby et al., 2009).

While the standard approaches have clearly been successful with some malignancies, the lack of therapeutic progress with others certainly suggests that new ideas are at least worth serious exploration.  Perhaps it is time to take fuller account of the evolutionary dynamics and ecology of tumor cells in the context of delivering cancer therapy.

References

Gatenby, R.A. A change of strategy in the war on cancer. Nature. 2009 May 28;459(7246):508-509.

Gatenby RA, Silva AS, Gillies RJ, Frieden BR. Adaptive therapy. Cancer Res. 2009 Jun 1;69(11):4894-903. PubMed PMID: 19487300.