National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
September 22, 2009 • Volume 6 / Number 18

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Cancer Research Highlights

Diabetes Drug Metformin Shows Promise as a Breast Cancer Treatment

Low doses of the commonly used diabetes drug metformin may be an effective treatment for breast cancer, primarily because the drug appears to target breast cancer stem cells, Harvard Medical School researchers reported online September 14 in Cancer Research. Cancer stem cells, also called tumor-initiating cells, are thought to be relatively rare cells that can give rise to new tumors and are resistant to standard cancer treatments.

In the study, the combination of metformin and the chemotherapy agent doxorubicin was more effective than either drug alone at eliminating cancer cells and cancer stem cells in cultured cell lines of four genetically distinct breast cancer types, including HER2-positive and triple-negative breast cancers. In a breast cancer mouse model, the drug combination eliminated tumors and prevented regrowth, whereas doxorubicin alone only reduced tumor size and did not prevent regrowth, and metformin alone had little effect.

“With both drugs, regression was quicker…and, more importantly, there was no relapse,” said senior author Dr. Kevin Struhl during a press briefing on the study.

When the researchers analyzed cell populations taken from the tumors of mice after three cycles of treatment, they found almost no cancer stem cells in the animals that received the drug combination but found the stem cells easily in tumors from mice given only doxorubicin. The highly beneficial effect of the combination treatment and the limited effect of either drug alone support the cancer stem cell hypothesis, Dr. Struhl said.

The results support previously published epidemiologic and laboratory studies that have suggested metformin has an anticancer effect, Dr. Jennifer Ligibel, a breast cancer researcher from Harvard University who was not involved with the study, said during the briefing. As a result, a large phase III clinical trial will test whether using metformin after standard treatment in women with early stage breast cancer can improve outcomes. The trial is being sponsored by NCI and coordinated by the National Cancer Institute of Canada. Trial investigators hope to start enrolling patients in the study next year, Dr. Ligibel said.

Hormone Therapy Linked to Risk of Death from Lung Cancer

Women who use combination hormone therapy to treat menopausal symptoms may be at an increased risk of dying from lung cancer. An analysis of data from the Women’s Health Initiative (WHI) study has found that, although the use of estrogen-plus-progestin therapy did not increase lung cancer incidence, it did increase the number of deaths from the disease, primarily from non-small cell lung cancer. The results appeared online September 18 in The Lancet.

“We have identified a new potentially lethal side effect of using estrogen-plus-progestin therapy over a relatively short period of time,” said lead investigator Dr. Rowan Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Postmenopausal women considering this therapy should be aware of the risk, especially those who are current or long-term former smokers, he added.

In 2002, the WHI ended early when an increased risk of breast cancer was found in women using combination hormone therapy compared with nonusers. Studies since then have shown that the increased breast cancer risk persists even after the hormones are stopped and that hormone use interferes with the detection of breast cancer, causing some women to have abnormal mammograms for at least a year. Hormone therapy has also been linked to an increased risk of ovarian cancer.

A potential mechanism to explain the new findings may be estrogen’s ability to stimulate blood vessel growth (angiogenesis), the researchers said, noting that strategies to block the growth of tumor blood vessels are used in both lung and breast cancer treatment. Another factor in the lung cancer deaths may have been that hormones delayed the detection of lung tumors, as has happened in breast cancer.

An accompanying editorial agreed that women at risk of lung cancer should avoid hormone therapy and asked whether this treatment has “any role in medicine today.” In addition, Dr. Apar Kishor Ganti of the University of Nebraska Medical Center noted that because the WHI was a randomized controlled trial, which is the gold standard in medicine, the results should dispel any notions that hormones may have protective effects against lung cancer, as several retrospective studies have suggested.

Recently Discovered Virus Linked to Aggressive Prostate Tumors

A previously unknown virus was discovered in tumors from men with prostate cancer in 2006, but at the time it was not clear whether the virus played a role in the disease. That question remains unanswered, but a new report shows that the virus, called xenotropic murine leukemia virus-related virus (XMRV), is present in malignant prostate cells and is more commonly found in men with aggressive tumors.

A survey of more than 300 prostate tissue samples showed that the virus was present in 27 percent of the tumor samples and 6 percent of the benign control samples. Reporting their findings last week in the Proceedings of the National Academies of Sciences (PNAS), the researchers also confirmed the initial classification of the virus as a type of gammaretrovirus. These pathogens can cause cancer in animals, but they have not yet been shown to cause cancer in people.

“The most important question now is does this virus cause cancer or not, and there are a few different ways to answer this question,” said lead investigator Dr. Ila Singh of the University of Utah. Her group is looking at prostate cancers to see whether viral DNA is integrated near human genes involved in growth. If so, the viral DNA may have activated the growth-promoting genes improperly and contributed to tumors.

If the viral DNA is positioned next to the same growth-promoting gene in each of a tumor’s cells, indicating the outgrowth of a clone, then the tumor could have originated from a single infected cell and this would be strong evidence of causation, Dr. Singh said.

The researchers are also investigating how the virus might be transmitted from person to person by analyzing seminal and cervical fluids and developing a blood test to check for the virus. If the virus does play a role in cancer, the most productive strategy for combating the problem would be to prevent infection, said Dr. Singh.

XMRV could potentially be a marker for identifying patients with aggressive forms of the disease who require appropriate treatment, she noted. Currently, there is no reliable way at the time of diagnosis to distinguish aggressive tumors from indolent forms of the cancer that may never cause harm.

Fat Cells Interfere with Chemotherapy for Leukemia

Research has indicated that obese children have a greater likelihood of relapse following chemotherapy to treat acute lymphoblastic leukemia (ALL). To investigate potential biological mechanisms behind this observation, researchers from Childrens Hospital Los Angeles tested the interactions between adipose (fat) tissue, ALL cells, and chemotherapy. The results, published online September 22 in Cancer Research, showed that adipocytes (fat cells) interfere with normal chemotherapy-induced apoptosis (cell death).

In an experiment using a mouse model of ALL, 7 of 12 obese mice developed progressive leukemia during or after treatment with the chemotherapy drug vincristine, compared with only 3 of 12 normal-weight mice. Numerous leukemia cells were found in the fat pads of all the mice, indicating that “adipose tissue can be a sanctuary site for leukemia during vincristine treatment,” stated the authors.

Culturing ALL cells with adipocytes protected the cancer cells from the effects of four different chemotherapy drugs, including vincristine. This effect was independent of whether the fat cells were in physical contact with the cancer cells.

The researchers also measured expression of several proteins involved in apoptosis in ALL cells grown with and without adipocytes, finding that the adipocytes increased the expression of two “survival genes” that prevent apoptosis in ALL cells, even during treatment with vincristine.

“Our findings show that obesity can directly impair the antileukemia efficacy of the first-line chemotherapy drug vincristine. This effect is likely due in part to adipocytes interacting with leukemia cells,” concluded the authors.

Hepatitis B Vaccine Lowers Risk of Liver Cancer

A universal childhood vaccination program against the hepatitis B virus (HBV) substantially lowered the number of cases of liver cancer among children and young adults aged 6 to 19, according to a study in Taiwan published online September 16 in the Journal of the National Cancer Institute.

Chronic HBV infection is considered the most important risk factor for developing liver cancer. Researchers from the National Taiwan University Hospital reviewed follow-up data on 1,958 liver cancer patients diagnosed between ages 6 and 29, most of who were born after Taiwan launched a national HBV childhood vaccination program in 1984. They found that only 64 of the patients with liver cancer had received the HBV vaccine, whereas 444 of the patients had not been vaccinated.

“These data suggest that the effectiveness of the universal HBV immunization program to prevent hepatocellular carcinoma has extended beyond childhood and into young adulthood over the past two decades,” the authors wrote.

Among the few vaccinated individuals who developed liver cancer, the two major possible causes were: the individuals did not receive enough doses of the HBV vaccine (three doses are required for full effect), or some individuals born to HBV-infected mothers were not given the first dose of vaccine soon enough after birth to prevent mother-to-child transmission of the virus, the researchers concluded.

“Further efforts to completely interrupt maternal transmission are crucial in eradicating HBV-related hepatocellular carcinoma,” the scientists wrote. They recommended improving rates of initial HBV vaccine injection within 24 hours after birth in infants of high-risk mothers.

In the United States, a national strategy to eliminate HBV infection through education and vaccination was implemented in 1991. As a result, the rate of new HBV infections has declined by approximately 82 percent, with the greatest decline among children born since 1991. As part of the U.S. strategy, the CDC’s Advisory Committee on Immunization Practices has issued immunization guidelines for the vaccination of infants and children.