May 19: "Foundations"

Meeting minutes Mon 5/19/08

Key points of consensus, controversy, and uncertainty:

In the view of this group, there is a general consensus in cancer biology that somatic cellular evolution does occur, as proposed during the 1970’s (1, 2). However, there is less agreement on the implications of this recognition. The participants in this workshop thought that somatic evolution should be a research focus and an organizing principle in cancer biology. However, they were also aware that this stance is not shared by all. Although the hypothesis of somatic evolution is rarely questioned or critiqued in the literature, it is not frequently invoked as an explanatory principle, and indeed is rarely discussed in many contexts where it might be relevant. This group perceived it to be a common (and flawed) view that although somatic selection may occur, it is usually safe to ignore in explaining cancer dynamics. This was seen as an orthodoxy that should be challenged.

For further clarification: There is a consensus in cancer medicine that single-drug therapies are not very effective (is this due to acquired resistance?) Acquired drug resistance is often observed, and is an important obstacle to successful therapy (true?).

Many workshop participants ascribed the appearance of drug resistance to the effects of Darwinian selection on heterogenous populations of cancer cells, as cytotoxic drugs kill off more vulnerable cells, thereby freeing up space and resources for more resistant cells which then proliferate in drug-resistant clonal expansions. The perception here, though, was that this explanation for the source of drug resistance is a minority view. Many alternative explanations have been offered for the emergence of drug resistance during cancer therapy, and there is little consensus in the broader community of cancer biologists. Because of the limitations of single-drug therapies, there was considerable interest in the strategy of multi-drug cocktail therapies. Analogies were suggested to the case of acquired resistance to the drug AZT by HIV virus. Here, somatic evolution of the virus was blamed for the emergence of acquired résistance. An evolutionary analysis based on mathematical models suggested that a multi-drug cocktail would curtail the somatic evolution of resistance and forestall relapse. [** ref – Perelson & Ho ?]. The approach was dramatically successful, converting AIDS from a death sentence to a manageable chronic disease. Discussants wondered why trials of multi-drug cocktails have not met with the same kind of dramatic success in cancer therapy, and suggested that a detailed study of the parallels and differences between the two cases might be illuminating.