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Published September 18, 2007 | Published
Journal Article Open

Targeting the absence: Homozygous DNA deletions as immutable signposts for cancer therapy


Many cancers harbor homozygous DNA deletions (HDs). In contrast to other attributes of cancer cells, their HDs are immutable features that cannot change during tumor progression or therapy. I describe an approach, termed deletion-specific targeting (DST), that employs HDs (not their effects on RNA/protein circuits, but deletions themselves) as the targets of cancer therapy. The DST strategy brings together both existing and new methodologies, including the ubiquitin fusion technique, the split-ubiquitin assay, zinc-finger DNA-recognizing proteins and split restriction nucleases. The DST strategy also employs a feedback mechanism that receives input from a circuit operating as a Boolean OR gate and involves the activation of split nucleases, which destroy DST vector in normal (nontarget) cells. The logic of DST makes possible an incremental and essentially unlimited increase in the selectivity of therapy. If DST strategy can be implemented in a clinical setting, it may prove to be curative and substantially free of side effects.

Additional Information

© 2007 The National Academy of Sciences of the USA. Contributed by Alexander Varshavsky, July 12, 2007 (received for review July 6, 2007). Published online before print September 10, 2007, doi: 10.1073/pnas.0706546104. I thank Bert Vogelstein, Christopher Brower, Michael Grunstein, and Cheol-Sang Hwang for their helpful comments on the paper. This study was supported by National Institutes of Health Grants GM31530 and DK39520. Author contributions: A.V. designed research, performed research, analyzed data, and wrote the paper. The author declares no conflict of interest.

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