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May 4, 2006

40 years later, cancer researcher’s big idea may prove true

Nearly 40 years ago, Dr. Lawrence Loeb had a remarkable idea about cancer. It took him quite a while, but he and his colleagues may have proven it.

Most types of cancer are believed to begin with a random genetic mutation that makes a normal cell go horribly awry. That mutated cell then replicates itself much more quickly than normal cells, and the resulting overpopulation of cells becomes a tumor. More random mutations pop up in the new cells, and those mutations help make the tumor malignant.

But Loeb had another idea — what if the cancer cells changed somehow, and became much more likely to mutate? These “mutator” cells would develop dangerous genetic mutations at a much faster rate than normal cells, which might account for the high number of mutations seen in tumor cells.

Since the technology of cancer genetics has dramatically improved, Loeb and his colleagues have only recently been able to test this hypothesis. They found that tumor tissue had random mutations up to 100 times higher than in normal tissue from the same patient. The “mutator” hypothesis seems to be correct.

Now for the bad news: if cancer cells do indeed become “mutator” cells, traditional chemotherapy and other drugs may never be very effective against advanced tumors.

“This is very bad news, because it means that cancer cells in a tumor will have mutations that protect them from therapeutics,” Loeb explained.

A chemotherapy drug may target a particular oncogene, which is a gene that affects the malignancy of a particular cell. But if cancer cells are mutator cells, a single tumor may have cells with many different types of oncogenes and drug-resistant genes.

That chemotherapy drug may kill off some of the cancerous cells, but millions of other cells in the tumor will live on. To be effective, a chemotherapy treatment may have to target more than one oncogene — so-called combination chemotherapy.

Not all of the news is bad, though. Loeb believes this research may eventually help physicians determine the stage and malignancy of a tumor by measuring the number of its mutations. The more mutations, the further along the tumor may be in its development to malignancy or metastasis.

Loeb’s work may also lead to a discovery of why cancer cells are becoming mutator cells. If scientists understand what happens in a cancer cell that makes it become a mutator, they might be able to prevent that from happening in other cells, or slow down the mutation rate.

“The idea is that if you might normally get exposed to something in the environment at 20 years old that would give you cancer by age 55, then if we cut the mutation rate in half, you might not get cancer until age 90, and you may even die of something else before that,” Loeb explained.

Loeb will discuss these results and the future of his research on cancer mutations in the Distinguished Science in Medicine Lecture, from noon to 1 p.m. on Thursday, May 18, in Hogness Auditorium, room A-420 in the UW Health Sciences Building.

Loeb is professor of pathology and biochemistry, and director of the Joseph Gottstein Memorial Cancer Research Laboratory in the Department of Pathology. His work is supported by the National Cancer Institute, the Ellison Medical Foundation, and the Alhadeff family in Seattle.