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You are here: Home Archived RFAs and PQs Given the appearance of resistance in response to cell killing therapies, can we extend survival by using approaches that keep tumors static?

2011 RFA Links and Provocative Questions  

PQ - 21
Given the appearance of resistance in response to cell killing therapies, can we extend survival by using approaches that keep tumors static?

Background: One of the most disappointing features of the development of new targeted therapeutics is how routinely drug resistance emerges. Evolutionary theory suggests that strong selection will always result in the emergence of resistant populations as long as some portion of the stressed population can adjust to the selective pressure. Similar theories also suggest that lessening the selective pressure to a level that seeks to hold the population in check may succeed at least for extended periods of time. Evolutionary fitness suggests that many mutations that arise after selection for cell killing are likely to be slightly deleterious in nature. While strong selection will easily let the mutated population emerge, if the selection is modest, the population may develop a new balance that reflects a combination of original tumor cells, dying tumor cells, and minor populations of the drug-resistant tumor cells whose fitness is impaired. Other types of selective pressures also may be valuable in these settings. For example, developing and using drugs that select for outcomes that are not solely inducers of cell killing may help establish a balance that would help create tumor stasis rather than strong selection for drug resistance. This Provocative Question suggests we should test the validity of these approaches as novel means to treat cancer. Ultimately, this may not produce a cure for a particular cancer but rather a method to treat cancer as a chronic disease.

Feasibility: Testing this theory is best done in animal models. Existing agents at low doses may provide good test cases; however, agents that induce other outcomes besides cell killing also should be considered, perhaps in combination.

Implications of success: These approaches present novel ideas for cancer therapy, but they highlight the importance of making sure we know what outcome for cancer patients is ultimately most useful. Living for some time with a debilitating tumor may be preferable to a rapid tumor regression with an almost certain drug resistant relapse.

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