PQD - 1 How does the selective pressure imposed by the use of different types and doses of targeted therapies modify the evolution of drug resistance? Background: One of the most disappointing features of the development of 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 varying the selective pressure will change the kinds of tumor cells that will emerge. Since this is a central issue for modern day cancer biology, it is important to learn how selective pressure from drugs with different mechanisms of action for the same target, agents with a wide range of target inhibition and PK/PD properties, and therapies given at different doses affect the emergence of resistant tumor cells. Evolutionary theory also suggests 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 studies show that most mutations that arise after selection are slightly deleterious in nature. Thus, mutant cells typically proliferate slower than the parental population. While strong selection will easily let the mutated cells emerge, if the selection is balanced correctly, evolutionary biology principles suggest that populations may emerge that contain a combination of sensitive parental cells and populations of the drug-resistant cells whose fitness is impaired. This Provocative Question seeks to understand how selective pressure imparted by drug treatment drives tumor evolution. Potentially interesting questions include: Do weaker selective pressures modify the timing and characteristics of emerging resistant clones? Do the relative IC50s or other characteristics of various drugs for targeted oncoproteins change the characteristics of tumor evolution? How does the fitness of resistant clones compare to parental populations? Can an evolutionary stable population of parental tumor cells and resistant clones be established by adjusting the selective pressure imposed by the drug? How do cytostatic and cytotoxic drugs compare when measuring tumor evolution and the emergence of resistant cells? How do combinations of agents affect the dynamics of tumor evolution? Feasibility: Testing these issues is best done in animal models. Existing agents with various properties can be compared and provide good test cases. Even agents that induce outcomes other than cell killing also could be considered, perhaps used in combination. Implications of success: These approaches present novel and challenging 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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