Increasing Genomic Stability to Decrease Cancer

Cancer can be boiled down to a question of stability. "Genomic instability is, in essence, the final common denominator in the ... evolution of cancer," comments Errol C. Friedberg, professor of pathology at University of Texas Southwestern Medical Center at Dallas. Defects to a cell's genome--whether they be mutations or damage caused by ultraviolet (UV) rays--that don't get fixed through DNA repair mechanisms will be passed on to new cells, he notes. "Anybody interested in understanding the pathogenesis of cancer wants to understand how genomic stability is maintained," Friedberg continues. "Anything that is important in maintaining genetic stability is probably important in protecting your cells against cancer. Any kind of gene defect that promotes genomic instability probably is a cancer-predisposing gene of some kind." Manipulating repair systems could restore stability to the genome and reduce cancer risks, notes James Cleaver, professor of dermatology at the University of California at San Francisco. The following are some potential approaches: Gene therapy. Cloning the genes from seven types of xeroderma pigmentosum (labeled XP A through G) has led to in vitro experiments that restore the nucleotide excision repair machinery, which is disabled by the two defective copies of one of the seven genes. Putting a functioning XPA gene into an XPC cell won't help the cell repair damage caused by UV light, but putting in the correct gene will. However, even in vitro, the correction is only transient. Longer-term expression has been achieved in vitro through vectors with selectable markers, but directing that expression and regulating it in vivo remains a problem that plagues the field of gene therapy. "Once the gene is in, it's in. It's hard to take it out again. And if you put it in the wrong place or did the wrong thing, you're in trouble." concludes Kenneth Kraemer, research scientist at the National Cancer Institute. Protein therapy. Perhaps a quicker fix, for XP at least, lies on the surface. AGI Dermatic Inc., of Long Island, N.Y., has put a bacterial DNA repair gene into a liposome lotion. The cream, in Phase III trials now, may give XP patients a way to repair DNA damage caused by UV rays. Kraemer compares the approach to providing a diabetic with insulin shots because both use endogenous proteins to deal with the symptoms of a disease. Small molecules. Friedberg notes that pharmaceutical companies are interested in targeting the DNA repair pathway. "It's complicated. It's not obvious exactly how you do this because there are many DNA repair pathways," Friedberg notes. "Our understanding of the details of how various DNA repair pathways work is pretty complete. There are many potential drug targets out there. The problem is the same as it is with any drug--which is how do you get specificity so that you inhibit what you're trying to inhibit in the tumor and not in the normal tissue at the same time?" Cleaver adds that small-molecule drugs may be more viable once a clearer link is drawn between signal transduction and DNA repair. "Since these repair processes feed into many cellular signal transduction pathways, interfering with some of these may actually prevent some of the genomic instability that is a consequence." Screening. The general population likely has variations in its DNA repair machinery, although not as dramatic as the complete loss of repair manifested in some XPs. Screening for such variations could help prevention, perhaps simply by warning people whose nucleotide excision repair machinery isn't operating at full capacity to use more sun protection. "We are probably at different risks for different cancers based on what our exposure is," Friedberg notes. Screening, which Friedberg refers to as "the genomics of the future," will also help pharmaceutical companies understand variations in response to drugs. "There are presumably polymorphisms in genes, minor changes in the genome, which don't necessarily cripple a protein or a biochemical pathway but put it at a disadvantage so that you as an individual are worse off even if you don't have any disease." Chemotherapy. DNA repair may be the "Achilles' heel" of a tumor, remarks Richard Fishel, professor of genetics and molecular biology at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia. Knowing more about what kind of repair defects a tumor has could help better target chemotherapy. "If you treated a tumor that was mismatch-repair defective with an alkalating agent ..., cells would be resistant to that." The trick may be finding which of a multitude of DNA repair pathways have been damaged, Fishel continues. Pathways to the tumor could include problems in mismatch repair, nucleotide excision repair, base excision repair, or recombination repair. "It could be subsets of any of those guys," Fishel notes. "You have to figure out which one it is. You have to figure out the common denominator so that you can target your therapeutic."

Increasing Genomic Stability to Decrease Cancer

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