National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
August 10, 2010 • Volume 7 / Number 16

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Cancer Research Highlights

Bone Drugs Do Not Appear to Increase Esophageal or Gastric Cancer Risk

Contrary to previous reports, researchers in the United Kingdom and at NCI have found no significant link at any level of use between oral bisphosphonates, drugs used to treat or prevent osteoporosis and bone-density loss, and esophageal or gastric cancer. The findings were published online August 10 in the Journal of the American Medical Association.

Dr. Chris Cardwell of Queen’s University Belfast and his colleagues analyzed medical data from more than 80,000 patients listed in the UK General Practice Research Database, half of who had been treated with bisphosphonates between 1996 and 2006 and half who had not used bisphosphonates. The patients were predominantly female (81 percent), with an average age of 70, and the follow-up time was 4.5 years for the bisphosphonate group and 4.4 years for the control group.

The rates of esophageal and gastric cancer were similar in both groups. Among the 41,826 people who took oral bisphosphonates, 116 developed gastric or esophageal cancer, compared with 115 people in the control group.

In January 2009, Dr. Diane Wysowski of the FDA urged caution when prescribing oral bisphosphonates to patients with preneoplastic lesions in the esophagus and called for studies of the association between bisphosphonates and esophageal cancer. However, in view of the new findings, “these drugs should not be withheld, on the basis of possible esophageal cancer risk, from patients with a genuine clinical indication for their use,” the researchers wrote.

Immune Cells’ Anticancer Abilities May Be Hampered by High Lipid Levels

In both mice and humans with cancer, dendritic cells, which are important components of the immune system, tend to have high lipid levels that significantly hamper their ability to direct other immune cells to attack cancer cells, a team of U.S. researchers reported. The research team also showed that a drug that interferes with the synthesis of these fat molecules restores dendritic cells’ ability to stimulate an antitumor response. The study was published in the August 2010 Nature Medicine.

Dendritic cells take up and process proteins and other molecules made by cancer cells (as well as viruses, bacteria, and other foreign bodies) and “present” them as antigens to other immune cells, so they can elicit an attack. Dr. Dmitry Gabrilovich from the H. Lee Moffitt Cancer Center and colleagues showed that dendritic cells in both mouse models of cancer and human tumor samples had significantly higher lipid levels—specifically triglycerides—than those from healthy mice and humans.

Dendritic cells with normal lipid levels generated a robust immune response, whereas the response generated by dendritic cells with elevated lipid levels was much weaker. Further experiments demonstrated that dendritic cells with elevated lipid levels had “profound defects” in their ability to take up and process antigen material, the researchers wrote.

In mice, treatment with a drug that interferes with the synthesis of fatty acids, called TOFA, “decreased the presence of lipid-laden dendritic cells" and restored their ability to “stimulate allogeneic T cells,” they reported. Combining a cancer vaccine with TOFA significantly shrank tumors, whereas the vaccines given alone had very little antitumor effect.

The findings suggest a new potential avenue for cancer immunotherapy, wrote Drs. Laurence Zitvogel and Guido Kroemer in an accompanying editorial. “Interfering with triglyceride accumulation in [dendritic cells] might constitute a promising strategy to restore anticancer immune responses and improve the efficacy of therapeutic vaccinations and conventional chemotherapies,” they concluded.

microRNA May Regulate Growth of Tumor Blood Vessels

The growth of blood vessels that supply tumors with essential nutrients may be regulated in endothelial cells by a small RNA molecule, or microRNA, a new study suggests. Researchers identified a microRNA called miR-132 that appears to act as a molecular switch for endothelial cell growth, causing the cells to transition out of their normal resting state and form new blood vessels (angiogenesis). The study, which could lead to a strategy for preventing angiogenesis and potentially for treating cancer, was published online by Dr. David Cheresh of the University of California, San Diego, and his colleagues August 1 in Nature Medicine.

Endothelial cells are among the least proliferative types of cells in adults, but they can be activated in response to certain cues, such as growth factors. Suspecting that microRNAs, which are known to regulate genes, might play a role, the researchers profiled microRNAs in a stem cell model of human vascular development and identified miR-132 as highly upregulated during the development of blood vessels. They then confirmed that miR-132 expression was also highly elevated in benign lesions of blood vessels, or hemangiomas, and in the blood vessels of human tumors, but was not detectable in normal blood vessels.

A molecular pathway analysis revealed that miR-132 suppresses the expression of a gene that encodes the protein p120RasGAP, which is a negative regulator of the protein Ras. Ras is frequently altered in cancer, so targeting miR-132 could be a way to intervene in an important pathway, the researchers said. And because miR-132 is found primarily in endothelial cells, these strategies would likely be specific to these cells, they noted.

As a proof of principle, the researchers used nanoparticle technologies they have developed to deliver an inhibitor of miR-132 directly to the vasculature of tumor-bearing mice. This treatment resulted in the blockade of tumor angiogenesis and tumor growth. Moreover, in mice with retinal disease that featured the growth of new blood vessels, direct injection of the anti-miR-132 into the eye was able to suppress angiogenesis in the retina.

“We essentially turned off the angiogenic switch during angiogenesis,” said Dr. Cheresh. The preponderance of growth in these cells was reduced, making it feasible to apply this kind of approach to patients with cancer and retinal diseases characterized by extensive angiogenesis, he added. 

Many U.S. and Canadian Oncologists Unprepared to Use Cost-effectiveness Data in Practice

Despite broad differences between their nation’s health care systems, Canadian and U.S. oncologists have similar opinions about how drug costs and comparative effectiveness should factor into decisions about patient care, report the authors of a recent survey. (The Canadian government funds health care, whereas the U.S. government does not.) The survey also revealed that oncologists in both countries do not feel adequately prepared to discuss treatment costs or comparative effectiveness with their patients. The results appeared online August 9 in the Journal of Clinical Oncology.

Nearly 800 randomly selected members of the American Society of Clinical Oncology took part in the survey, which was funded in part by the California HealthCare Foundation. In Canada, surveys were offered to members of national medical and oncology organizations, and 138 responses were received.

The survey showed that most physicians in both countries believe that patients should have access to effective cancer treatments only if the treatments provide a “good value for [the] money,” though significantly more Canadians felt this way than Americans (75 percent versus 58 percent, respectively). The threshold for a “good value” was higher for Canadians than for Americans, but most oncologists in both countries believe that a ratio of less than $100,000 per life-year gained was appropriate. However, less than half of the oncologists (42 percent of the Americans and 49 percent of the Canadians) felt prepared to factor cost-effectiveness into their treatment decisions.

Clinicians in both countries did not favor government or insurance companies making decisions about whether specific drugs provide good value, but they did favor physicians and nonprofits doing so; and the majority in both countries felt that more government price controls for cancer drugs are needed, though this opinion was less common in the United States (57 percent) than in Canada (68 percent).

The authors noted the possibility of biases in their results due to different survey methods used in each country. But they concluded that because the opinions of the two groups were so similar, and because oncologists in both countries face rapidly rising costs of new cancer medications that may or may not be covered by health insurers, oncologists in the United States and Canada should collaborate on strategies to face the challenges ahead.

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