CANCER THERAPEUTICS: SMART AND SMARTER

Conventional cancer therapeutics target rapidly proliferating cells by introducing widespread damage into DNA, but do so nonselectively. damaging normal as well as malignant cells As a result, maximally tolerated doses are often not curative and the treatment regimens are often highly toxic In recent years targeted smart therapies hove been developed to provide selective tumor cell killing and reduced toxicity, with striking success in a small number of cases This approach has been constrained, however, by the difficulty of identifying molecular targets unique to malignant cells, the small number Of tumor types targeted by a given drug, and the tendency of malignant cells to escape through further changes in the targeted protein or the development of alternative signaling pathways in the tumor cells These limitations, combined with the high cost of drug development, seem likely to reduce the eventual impact of such therapies, despite the excitement they hove generated in the scientific and pharmaceutical communities A conceptually more powerful approach Would be to tot-get on innate DNA damage response pathway, common to all cell types, activated by dysregulated cell growth to selectively kill malignant cells An inducible QNA damage response first identified in bacteria and termed the SOS response appears to provide this opportunity In mammalian cells, telomere-based mechanism functions to protect normal cells against repeated exposures to DNA-damaging agents and to eliminate damaged cells, but is ineffective in malignant cells Telomere homolog oligonucleotides, termed T-oligos, appear to mimic single-stranded telomeric DNA, interact at telomeres with the Werner protein and initiate signaling through the ATM and ATR kinases The p53 tumor suppressor protein and many other DNA damage response proteins are then activated and/or upregulated, leading in normal cells to a variety of protective responses, but in malignant cells to apoptosis or senescence, depending on cell type Surviving cells undergo differentiation, lose angiogenic capacity and increase their susceptibility to low-dose conventional chemotherapeutics Overall, at least in mouse models, there is a broad and coordinated response that greatly reduces tumor burden without detectable adverse effects on normal cells and tissues These preclinical observations suggest the possibility of a next generation of smarter therapies that rely on on SOS-like response, evolutionarily perfected to protect higher organisms from malignancy