Question ID: WS-48
Submitted by: Titia de Lange
February 7, 2011
Steve Elledge/Titia de Lange: How can we exploit the past and/or ongoing genome instability in cancer? The recent sequencing data and other high resolution genome analyses has revealed that the frequency of mutations and genome rearrangements in solid tumors is much greater than previously appreciated. It seems likely that this rampant genome instability reflect a change in chromosome husbandry (DNA repair, chromosome segregation, telomere protection, etc), allowing the acquisition of a mutator phenotype that is either permanent or episodic. The data also predict that most cancers have undergone adaptive changes that allow them to tolerate the mutator phenotype (e.g. frequent chromosome mis-segregation, deficiency in a repair pathway) and its consequences (e.g. gene dosage alterations, high frequency of deleterious mutations). Such adaptive changes in cell physiology can be exploited as shown by the use of PARP inhibitors in BRCA1/2 breast cancer. Further identification of these adaptations and their associated vulnerabilities provides a fertile ground for new therapeutic interventions.
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