Research: Gene therapy with cellular guardian

Research using lab mice suggests that types of cancer can be forced into retreat by restoring the functions of a key guardian gene.

The spotlight is being placed on the p53 gene; the gene most commonly linked to cancer.
When functioning normally, p53 is alerted to the presence of an abnormal cell and unleashes one of two defensive processes -- apoptosis, in which the cell is instructed to commit suicide, and senescence, in which the cell's growth is arrested.

But inherited mutations in p53 can cause it to malfunction or it can be blocked by a protein called MDM2, and with this important suppressor out of the way, tumors then proliferate.

Two papers, published by the British journal Nature, used either gene therapy or a molecular technique called RNA interference to restore the function of p53 in mice with established cancer.

The tumors sharply regressed through senescence or apoptosis depending on the type of cancer cell. One of the studies, entailing mice with liver tumors, also found that inflammatory cytokines, a component of the immune system, were also unleashed to help clear the tumor.

The work "opens new therapeutic avenues against cancer," such as drugs to block MDM2 or other p53 inhibitors, and -- more distantly -- gene therapy to fix mutant versions of the p53 gene, a commentary in Nature says.

The papers are lead-authored respectively by Scott Low of Cold Spring Harbor Laboratory in New York and Tyler Jacks of the Massachusetts Institute of Technology (MIT).

Those authors sounded a note of caution about the success, saying that secondary tumors
sometimes emerged, apparently through resistance to the reactivated p53.

Research: Gene therapy using RNA

Two separate teams of researchers have found a way of switching off critical genes within a tumour cell that would otherwise stimulate the spread of the cancer. Although the research is still at an early stage, scientists are describing the approach as potentially one of the most important developments since the former US president Richard Nixon declared his "war in cancer" in 1971.

Doctors often describe cancer as a genetic disease because of the role played by genes in causing the uncontrolled proliferation of a cancerous cell into a tumour. The radical approach is to use molecules of RNA - a substance similar to a gene's DNA - to "silence" or switch off certain key genes known to be involved in the growth of tumours.

One team at the University of Oxford has shown in a laboratory study that it is possible to use large molecules of RNA to switch off a gene responsible for an enzyme called dihydrofolate reductase (DHFR), which is essential for the rapid proliferation of tumour cells.

Another team, based in the German city of Tübingen has used smaller molecules of RNA in an animal study to switch off a separate gene known to be involved in the rapid growth of brain tumours.

Alexandre Akoulitchev, a senior research fellow at Oxford, said that there is a growing consensus among cancer scientists that RNA molecules could generate new ways of treating the many different kinds of cancer that can affect the body. "There has been a quiet revolution taking place in biology during the past few years over the role of RNA," he said.

The Oxford team has shown that it is possible to use RNA to directly affect the genetic "switch" controlling the gene for DHFR. When it is switched off, the rapidly dividing cancer cells are starved of a vital building block - a chemical called thymine. "Inhibiting the DHFR gene could help to prevent the growth of neoplastic cancer cells - ordinary cells which develop into tumour cells - such as in prostate cancer cells," Dr Akoulitchev said. "In fact, the first anti-cancer drug, Methotrexate, acts by binding and inhibiting the enzyme produced by this gene," he said. The Oxford study is to be published in the journal Nature.

Another approach is being adopted by Professor Michael Weller, medical director of general neurology at the University Clinic in Tübingen, who is using smaller molecules of RNA to silence a gene that otherwise protects brain tumours from being attacked by the body's immune system.

In experiments on mice with malignant brain cancer all the tumours decomposed completely because they were no longer being protected by the silenced gene - known as TGF-beta.

"We saw the tumours grow, then we saw them regress. I've been working on this for 10 years and it's the only technology where we've reliably produced cures for the animals," Professor Weller said.

The two American scientists who discovered RNA-interference, Andrew Fire, of Stanford University, and Craig Mello, from the University of Massachusetts, won last year's Nobel Prize in medicine.

Research: DCA

Scientists and patients are buzzing about DCA, an existing drug newly recognized as a potentially powerful cancer treatment. But, of course, more research is needed.

By Jerry Adler, Newsweek

Jan. 23, 2007 - There are no magic bullets in the fight against cancer: that's the first thing every responsible scientist mentions when discussing a possible new treatment, no matter how promising. For decades, research has emphasized the differences among the many kinds of cancer, their origins in the complex interplay between genes and environment, and the development of ever more sophisticated and tightly focused therapies. Everyone knows that cancer will not be cured the way antibiotics cure a staph infection.

If there were a magic bullet, though, it might be something like dichloroacetate, or DCA, a drug that kills cancer cells by exploiting a fundamental weakness found in a wide range of solid tumors. So far, though, it kills them just in test tubes and in rats infected with human cancer cells; it has never been tested against cancer in living human beings. There are countless compounds that can do the same thing that never turn into viable treatments. But DCA has one big advantage over most of those: it is an existing drug whose side effects are well-studied and relatively tolerable. Also, it's a small molecule that might be able to cross the blood-brain barrier to reach otherwise intractable brain tumors. Within days after a technical paper on DCA appeared in the journal Cancer Cell last week, the lead author, Dr. Evangelos Michelakis of the University of Alberta, was deluged with calls and e-mails from prospective patients—to whom he can say only, “Hang in there.” There are no magic bullets against cancer.

Still, Michelakis may be onto something important. "The work is very interesting, from a conceptual standpoint," says Dr. Dario Altieri, director of the cancer center at the University of Massachusetts Medical School in Worcester. DCA is a remarkably simple molecule related to acetic acid, better known as vinegar. It acts in the body to promote the activity of the mitochondria, the cellular structures where glucose is oxidized to provide energy; its main pharmaceutical use has been to treat certain rare metabolic disorders. But the mitochondria have another function: they initiate apoptosis, the fail-safe process by which cells with damaged DNA destroy themselves before they can do damage. This goes on continually in the body. But when a cell turns cancerous, it begins processing glucose outside the mitochondria; the mitochondria shut down, and the cell becomes immune to apoptosis—immortal, until it kills its own host. Researchers have assumed that the mitochondria in cancer cells were irreparably damaged. But Michelakis wondered if that was really true. With his colleagues he used DCA to turn back on the mitochondria in cancer cells—which promptly died.

Remarkably, Michelakis isn't even an oncologist; he's a cardiologist who was studying pulmonary hypertension, a deadly condition in which the cells lining the walls of the blood vessels in the lungs inexplicably proliferate. His research suggested that DCA could help that, too, but the possibility that he might be on the track of a treatment for cancer was too tempting to pass up. One of the great things about DCA is that it's a simple compound, in the public domain, and could be produced for pennies a dose. But that's also a problem, because big drug companies are unlikely to spend a billion dollars or so on large-scale clinical trials for a compound they can't patent. So Michelakis and his colleagues Stephen Archer and John Mackey, with the support of the University of Alberta and the Alberta Cancer Board, are embarking on the process themselves, hoping to interest foundations or private philanthropists in underwriting their research.

They have one advantage: because DCA is already in use, they can combine Phase I trials, meant to establish safety, with Phase II, which look at whether the compound actually works. The first subjects, says Mackey, will probably be patients with breast, lung or colon cancers that have recurred after initial treatment—in other words, people without much hope of a cure. He would like nothing better than to offer them some hope. But again, he warns, in cancer, there are no magic bullets.