SYNERGISTIC ACTION
Scientists discover four genes that act together to spread cancer, find drugs to block them
Guardian gene forces cancer to retreat
PARIS
Research using lab mice suggests that certain 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, which is the gene most commonly linked to cancer.
When it functions normally, p53 is alerted to the presence of an abnormal cell and unleashes one of two defensive processes-apoptosis, in which the cell commits 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 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, involving mice with liver tumors, also found that inflammatory cytokines 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, an accompanying commentary said.
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.
Tiny molecule may become big player in cancer fight
MONTREAL
A small odorless, colorless, inexpensive, and relatively nontoxic molecule that is not patented or owned by any pharmaceutical firm could be used to treat several forms of cancer, Canadian researchers said.
The molecule dichloroacetate (DCA) causes a turnabout in most cancers, including lung, breast, and brain tumors, said Evangelos Michelakis and his colleagues at the University of Alberta in western Canada in their research published in Cancer Cell.
DCA repaired damage caused by cancer to mitochondria, about 2,000 units in every cell that convert food molecules into energy, causing "a significant decrease in tumor growth both in test tubes and in animal models." It did not affect healthy tissues, unlike most chemotherapies.
"I think DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells," Michelakis said.
Cancer cells suppress their mitochondria, which also regulates cell death, appearing to offer cancer cells a significant advantage in growth compared with normal cells, as well as protection from standard chemotherapy.
But DCA reverses this phenomenon.
"One of the really exciting things about this compound is that it might be able to treat many different forms of cancer, because all forms of cancer suppress mitochondrial function," Michelakis said.
Furthermore, the tiny molecule is easily absorbed in the body and can reach areas that other drugs cannot, such as beyond the blood-brain barrier, a membrane that controls the passage of substances from the blood into the central nervous system, to treat brain cancers, for example.
And the "relatively nontoxic" compound has been used to treat mitochondrial disease for decades, so it can be immediately tested in patients with cancer without first undergoing expensive initial clinical trials to determine if it is safe to use.
More numerous than thought
PARIS
The biggest-ever map of the DNA drivers for cancer suggests that a far higher number of genes may be implicated in this disease than was previously thought. An international consortium of scientists sequenced more than 500 genes suspected to play an important role in initiating or spreading cancer.
The scientists specifically looked for abnormalities in so-called protein kinase genes, which are like switches that control cell behavior, such as cell division. In a sift of 518 kinase genes implicated in 210 cancers, they found more than 1,000 of these mutations. Some of these were "driver" mutations that caused the tumors or helped them to develop; others were "passenger" mutations that were created as a result of sloppy cell replication and played no role in the disease.
Distinguishing between the culprit "driver" and the apparently harmless "passenger" will be the next big step, as this will pinpoint some of cancer's molecular pathways.
But the team is already confident that around 120 of the genes they screened have "driver" mutations. Most of these genes had not been fingered before as cancer culprits.
"It turns out that most mutations in cancers are passengers," said Andy Futreal of Britain's Wellcome Trust Sanger Institute. "However, buried among them are much larger numbers of driver mutations than was previously anticipated."
The mutations also give a fascinating insight into what caused the cancer in the first place. Their patterns provide a signature in DNA, perpetuated in the genetic code, that point to damage from sunlight or cancer-causing chemicals in tobacco. Other factors, though, remain to be decrypted.
Four genes linked to "silent killer"
PARIS
Scientists have uncovered four more genes that play a role in breast cancer, widening the portrait of one of the stealthiest slayers of women. Until now, only about 25 percent of the genes that are suspected to cause inherited breast cancer have been identified.
The new culprits-flawed versions of genes called FGFR2, TNRC9, MAP3K1, and LSP1-are believed to account for an additional four percent.
British-led researchers found them after sifting through the DNA of nearly 50,000 women, half of them healthy and half of them patients with breast cancer. Telltale "tags" of DNA code in the breast-cancer group highlighted the four genes.
Genetic causes account for between five and 10 percent of breast- cancer cases, with "lifestyle factors" such as smoking and environmental factors accounting for the rest.
Flawed versions of the four genes are common in the general population, said the paper published by Nature.
The good news, though, is that the genes are considered a relatively low hazard, meaning that women who have them run a comparatively small risk of developing cancer.
By contrast, the notorious breast cancer genes BRCA1 and BRCA2 are relatively rare in the population but women who have them run a high risk of the disease.
Diagnostic tests for BRCA1 and BRCA2 are helping to save many lives, as they alert women at risk to have regular breast scans.
Because the four newly identified genes are so common yet relatively low-risk, individual tests for them may be unsuitable, said Cancer Research UK, whose scientists led the massive investigation. However, "as more of these low-risk genes are found it may be possible to design tests for a combination of genes," it said. "This could help doctors make decisions about prevention, diagnosis, and treatment for women who inherit faults in one or more of these genes."
Much remains to be learned about the four genes, especially whether they react with each other or with lifestyle factors in a way that boosts the risk for some women, it added.
Combo treatment arrests metastasis
PARIS
Researchers have isolated a set of four genes closely linked to the growth of breast-cancer cells and their spread to the lungs. The findings suggest that combination drugs could inhibit these mutant genes from forming tumors and promoting metastasis.
In an experiment on mice injected with human cancer cells, "two drugs clinically available showed at least a tenfold reduction in the rate of growth of lung tumors" when administered together, said Joan Massague, a cancer biologist and lead author of the study.
Massague and a team of scientists at the Memorial Sloan-Kettering Cancer Center in New York City reported their findings in Nature.
The study showed that the four defective genes, acting "synergistically," formed "a tortuous and highly permeable network of blood vessels" in tumors. To confirm that the genes were acting together to spread the cancer, the researchers deactivated them in mice through genetic manipulation in breast-cancer cells that were metastasizing to the lungs. The result was an almost complete curtailment of growth and expansion.
Such genetic tinkering is not feasible as a form of therapy, Massague said.
The study also noted that there was a "division of labor" between different gene categories, with some involved exclusively in metastasis and others in fueling tumor growth.
There are many kinds of cancer, but all are characterized by the uncontrolled division of human cells that spread either by invading adjacent tissue or through metastasis. When normal cells are damaged beyond repair, they are programmed to self-destruct through apoptosis. But when cancer strikes, this mechanism fails to work, and the defective cells continue to multiply unchecked.
The four genes identified are already well known to cancer researchers, but this is the first study to clearly demonstrate how their combined effect accelerates the spread of cancer.
The study also tested the capacity of several drugs, known to inhibit the activity of each gene, to block cancerous growth.
Taken individually, the three drugs had little if any impact in halting the proliferation of cancer in mice injected with tumor cells, mirroring the results obtained through genetic manipulation. When combined, however, the cocktail reduced tumor growth by roughly 50 percent compared with mice deprived of any treatment. In human patients, breast-cancer tumors are removed surgically.
More significant, Massague said, was the tenfold reduction in growth obtained by targeting the genes that help cancer cells spread from the tumor in the mammary glands to the lungs.
The authors remain very cautious in describing the therapeutic potential of their findings. "It is not as simple as it sounds," explained Massague. "We are not talking about taking patients out of chemotherapy to do the tests-the question is how to combine current treatment with the drug combinations."
Clinical trials set to begin soon could yield preliminary results within a couple of years, he said. The implications of the study, he added, could extend well beyond breast cancer to other forms of the disease-such as colon and liver cancer-that involve the same genes and can metastasize to the lungs.
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