Targeting the Absence: Homozygous DNA Deletions As Immutable Signposts for Cancer Therapy

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Sep 12

PMID 17846424

Citations 18

Authors

Alexander Varshavsky

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Deletions of DNA in cancer and their possible uses for therapy.

Varshavsky A, Lewis K, Chen S Bioessays. 2023; 45(7):e2300051.

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