In challenge to personalized cancer care, DNA isn't all-powerful

Thu Dec 13, 2012 2:00pm EST
 
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By Sharon Begley

NEW YORK Dec 13 (Reuters) - The cancer cells were not behaving the way the textbooks say they should. Some of the cells in colonies that were started with colorectal tumor cells were propagating like mad; others were hardly multiplying. Some were dropping dead from chemotherapy and others were no more slowed by the drug than is a tsunami by a tissue. Yet the cells in each "clone" all had identical genomes, supposedly the all-powerful determinant of how cancer cells behave.

That finding, published online Thursday in Science, could explain why almost none of the new generation of "personalized" cancer drugs is a true cure, and suggests that drugs based on genetics alone will never achieve that holy grail.

Scientists not involved in the study praised it for correcting what Dr. Charis Eng, an oncologist and geneticist who leads the Genomic Medicine Institute at the Cleveland Clinic, called "the simple-minded" idea that tumor genomes alone explain cancer.

Calling the study "very exciting," she said the finding underlines that a tumor's behavior and, most important, its Achilles heel depend on something other than its DNA. Her own work, for instance, has shown that patients with identical mutations can have different cancers.

The core premise of the leading model of cancer therapy is that cells become malignant when they develop mutations that make them proliferate uncontrolled. Find a molecule that targets the "driver" mutation, and a pharmaceutical company will have a winner and patients will be cancer-free.

That's the basis for "molecularly targeted" drugs such as Pfizer 's Xalkori for some lung cancers and Novartis 's Gleevec for chronic myeloid leukemia. When those drugs stop working, the dogma says, it is because cells have developed new cancer-causing mutations that the drugs don't target.

In the new study, however, scientists found that despite having identical genetic mutations, colorectal cancer cells behaved as differently as if they were genetic strangers. The findings challenge the prevailing view that genes determine how individual cells in a solid tumor behave, including how they respond to chemotherapy and how actively they propagate.

If DNA is not the sole driver of tumors' behavior, said molecular geneticist John Dick of the Princess Margaret Cancer Centre in Toronto, who led the study, it suggests that, to vanquish a cancer entirely, drugs will have to target their non-genetic traits too, something few drug-discovery teams are doing.   Continued...