It's just over a decade since the oncology molecule p53 made its bow in the late 1980s. The p53 gene wears two hats: white as a tumor-suppressor; black as a cancer-pushing oncogene. Since oncogenes were discovered nigh onto 20 years ago, scientists have discovered at least 15 tumor suppressor genes and well over 100 oncogenes.

One of the latter is nicknamed MYC - short for myelocytomatosis virus. "It was a bird-borne, avian virus that caused leukemia and lymphoma," observed medical oncologist Dean Felsher at Stanford University. "A long time ago," he recounted, "many people found that these cancer-causing viruses contained oncogenes, which had a normal equivalent in humans, mice and every other living organism.

"MYC is not a tumor suppressor gene," Felsher pointed out. "In its normal persuasion, it's a protooncogene, which tells cells when to grow, when to replicate their DNA, and then divide. So if you don't have MYC in your tissues, it's very difficult for your cells to multiply.

"There are two ways for MYC to convert from a benign growth factor to a malignant tumor promoter," Felsher explained. "One is if it becomes massively overexpressed. Many people have made transgenic mice with MYC, and in all of them MYC stayed normal but overexpressed. There are also mutations in the MYC oncogene that cause it to be more cancer-causing," Felsher continued. "But the most important bad actor probably is when there is too much of it."

Felsher is senior author of a paper in the current issue of Science, dated July 5, 2002. Its title: "Sustained loss of a neoplastic phenotype by brief inactivation of MYC."

"The newsworthy part of this paper," Felsher told BioWorld Today, "was the fact that we could shut off an oncogene for a short period of time, and the cancer phenotype [an individual's observable characteristics] did not necessarily come back. Previously," he went on, "I and other people had shown that if you shut off an oncogene in an experimental cancer, it could reverse that cancer's phenotype. The surprising result was that turning the MYC gene back on does not necessarily result in the cancer coming back immediately."

Inhibiting MYC An Elusive Anticancer Target

"This very preliminary finding has two potential implications," Felsher went on. "One is for my colleagues who are trying to make drugs to treat cancer by turning off cancer genes. Even turning them off for a few days might be enough to change the cells, so if that cancer gene got reactivated, its tumor cells might die.

"The second implication is a practical one," he added. "If you made a drug that could completely inhibit the function of the MYC oncogene that I worked on, it might be very toxic, if administered for long periods of time. But should it turn out to be true - and this work is very preliminary - then turning off MYC for a few days would be enough to have an effect on the cancer. And it makes it much more likely that one could design a therapy in a way that would be less toxic to patients. But it's theoretical because there isn't right now, at this minute, a drug that would inhibit MYC. People are trying to develop such drugs, but there isn't a drug yet.

"I am trying to find such drugs," Felsher allowed, "although my main research focus is to understand when such a drug would work. Meanwhile, I'm trying to encourage other people, who have more resources. There are many biotech companies that on and off have been interested in making MYC a target."

Meanwhile, he and his co-authors are working with a complex strain of transgenic mice that can turn the MYC gene on and off at will. "Five years ago," Felsher recalled, "a German scientist named Bujard discovered that he could make transgenic mice in which he could turn genes on or off at will. His trick was based on the fact that Escherichia coli can conditionally regulate gene expression for antibiotic resistance. Bujard had the epiphany of realizing, Wow! Bacteria use molecular tricks for turning on a gene for resistance to the tetracycline antibiotic.' So I thought," Felsher recalled, What if my group here at Stanford took that molecular machinery and put it into mouse cells?'

"We could use mice that had MYC expressed in their tissues," he observed. "With that German machinery, we could turn the animals' oncogene expression on and off, whenever we felt like it. To perform this sleight of genes," Felsher explained, "we put the gene of interest next to an enhancer called the tetracycline response element. Then, by expressing the tetracycline transactivating protein in the tissue we cared about, wherever that gene came out it would bind next to the tetracycline response element, and cause it to be expressed." (That tetracycline system, Felsher noted, is a licensed technology his group obtained from Clontech Laboratories Inc., of Palo Alto, Calif.)

Reversing Cancer: An Open-And-Shut Case

In their in vivo experiments, Flesher and his team created those conditional transgenic mice carrying a MYC oncogene that selectively, inherently, gave rise to osteosarcoma - bone cancer. "The upshot of these in vivo experiments," Felsher recounted, "was that - totally to my surprise - not only could we shut off the cancer by switching off the oncogene, which we had already shown, but we didn't need to shut down the oncogene for long. Even if we switched it off for a few days, that was enough to have an effect on the cells. So in mice that were dying of bone cancer, I found that we could shut off MYC for 10 days, and they got better. And even if I allowed the MYC oncogenes to go back on, even if I knew that the tumor cells were still there, this cancer didn't come back very readily.

"Subsequent reactivation of MYC did not restore the tumor cells' malignant properties," he noted. "Instead, it induced their apoptosis - cell death. We found that by briefly tinkering with only one mutant oncogene, we could forever alter the course of the tumor. These results raise the possibility," Felsher concluded, "that transient inactivation of mutant MYC may be an effective therapy for certain cancers."