National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 13, 2012 • Volume 9 / Number 22

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Cancer Research Highlights

Drug May Reduce Cognitive Decline Following Radiation for Brain Metastases

A drug already approved to help improve cognition in some patients with dementia may limit declines in memory and cognitive function in patients who are undergoing whole-brain radiation therapy (WBRT) to treat cancer that has spread to the brain. Results from a clinical trial to test the drug, memantine (Namenda), in patients with brain metastases were presented October 28 at the American Society for Radiation Oncology (ASTRO) annual meeting.

More than 60 percent of patients with brain metastases who undergo WBRT experience problems with cognitive function within 4 months after completing treatment, explained the trial’s lead investigator, Dr. Nadia Laack of the Mayo Clinic Cancer Center, during a press briefing. The intent of the NCI-supported trial was to determine whether memantine could prevent memory decline in patients, rather than to test whether the drug improved progression-free or overall survival, Dr. Laack noted.

The phase III randomized trial, conducted by the Radiation Therapy Oncology Group and dubbed RTOG-0614, enrolled more than 550 patients, who received either memantine or a placebo during WBRT and for 6 months afterward. The researchers assessed participants’ memory and other cognitive functions, such as the ability to process information and make decisions, before and after treatment. Many patients in the trial died or had cancer that continued to progress, however, so after 24 weeks only 149 patients could be evaluated.

Patients whose disease progressed “often refused testing so, in effect, we were largely evaluating patients who had not progressed,” Dr. Laack explained in an e-mail message.

In patients treated with memantine, memory decline took longer to appear and was less severe, although the improvement was not statistically significant. However, the risk of cognitive decline fell 17 percent, a drop that was statistically significant.

“Although memantine was discontinued at 6 months, the effect on cognitive function was maintained for the duration of the trial, suggesting that memantine may be preventing radiation injury rather than simply treating cognitive dysfunction,” Dr. Laack said.

Based on the trial’s results, memantine will likely now be used as standard therapy for patients undergoing WBRT to treat brain metastases, she added. “We do feel that this is going to impact practice tomorrow and that, for future trials, memantine will be the standard against which other agents are tested.”

This study was funded in part by the National Institutes of Health (CA21661, CA32115 and CA37422, RTOG U10 CA21661, and CCOP U10 CA37422).

Brazil's Strong Antismoking Policies Credited with Saving Lives

Using a policy simulation model called SimSmoke, researchers have estimated that strong tobacco control policies implemented in Brazil between 1989 and 2010 cut the smoking rate nearly in half and saved almost 420,000 lives during that period. Dr. David Levy of Georgetown University's Lombardi Comprehensive Cancer Center and his colleagues published their findings November 6 in PLOS Medicine.

Using SimSmoke, the researchers looked at the effects of various tobacco control policies on the smoking rate in Brazil, which declined from 34.8 percent in 1989 to 18.5 percent in 2008. SimSmoke models the effects of tobacco control policies on smoking initiation and cessation rates and uses the changes in these rates to estimate smoking rates over time. 

The Brazil SimSmoke model showed that almost half of the 46 percent reduction between 1989 and 2010 was due to tobacco tax and price hikes. Smokefree air laws, restrictions on advertising, programs to help people quit smoking, media campaigns, and mandatory health warnings on tobacco packaging also contributed to the drop in smoking rates.

“This study indicates how powerful tobacco control policies are,” said Dr. Levy.

Brazil’s current tobacco control policies are projected to reduce the smoking rate from 16.8 percent in 2010 to 10.3 percent in 2050 and prevent an estimated 7 million premature deaths due to smoking. The model also showed that, if Brazil fully implemented policies recommended by the World Health Organization’s Framework Convention on Tobacco Control, the country’s smoking rate would fall to 6.3 percent by 2050, preventing 1.3 million more deaths. 

“Brazil’s accomplishments demonstrate that, even for a middle-income nation, reducing tobacco use is a ‘winnable battle’ that carries huge dividends in terms of reducing mortality and morbidity,” the researchers wrote. 

“There is now a ‘global laboratory’ of tobacco control,” said Dr. Michele Bloch, acting chief of NCI’s Tobacco Control Research Branch. “Studies from around the world allow countries to benefit from each other’s experience.”

This study was funded in part by the National Institutes of Health (UO1-CA97450-02).

Possible Cause of Doxorubicin-Induced Heart Damage Identified

The damage to heart tissue (cardiotoxicity) sometimes seen with the drug doxorubicin may be caused by the chemotherapy’s effects on an enzyme called topoisomerase-IIβ (Top2β). This finding, from experiments in mice led by Dr. Sui Zhang of the University of Texas MD Anderson Cancer Center, was published October 28 in Nature Medicine.

The results suggest that Top2β is “an essential driver of doxorubicin-induced cardiotoxicity,” the authors concluded. This knowledge could lead to the development of drugs that are less cardiotoxic than doxorubicin, as well as to tests that identify patients who are most at risk for heart damage associated with this drug, they said.

Doxorubicin’s anticancer effects are thought to be caused by its interactions with a related enzyme, called topoisomerase-IIα (Top2α). This enzyme is expressed in rapidly dividing cells, including cancer cells, but not in mature, nondividing cells. Top2β, on the other hand, is found in all cells, and the highest levels are found in mature cells.

Because doxorubicin also interacts with Top2β, the researchers proposed that the drug might damage mature heart muscle cells through its effects on this enzyme. For their experiments, the researchers genetically engineered mice to have heart muscle cells that did not express Top2β. 

When normal mice were exposed to doxorubicin, the researchers found changes in the gene expression of heart-muscle cells that were not found when mice with Top2β-deficient hearts were treated with the drug. Many of the changes occurred in cellular signaling pathways that regulate cell death (apoptosis) and the functioning of mitochondria, structures inside cells that produce most of the energy cells use.

When researchers measured the level of apoptosis in heart muscle cells to assess doxorubicin-induced damage to the heart, Top2β-deficient hearts had 70 percent fewer dying heart muscle cells than normal hearts after doxorubicin treatment. Moreover, mice with Top2β-deficient hearts had no decrease in heart function after 5 weeks of doxorubicin, whereas heart function in normal mice fell by 10 percent.

Drugs that specifically target Top2α and not Top2β “should be less cardiotoxic and, hence, more useful clinically,” they continued. And measuring Top2β expression could identify patients more likely to experience heart damage from doxorubicin. “These predictions can be tested in animals and humans,” they concluded.

This study was funded in part by the National Institutes of Health (CA102463).

Study Reveals New Mechanism of Action for Class of Targeted Therapy

Researchers have discovered a new way in which PARP inhibitors block cancer cell growth. The researchers also have found that three experimental PARP inhibitors, which were presumed to have similar activities, vary widely in their ability to kill cancer cells. The study, led by Dr. Yves Pommier of the Laboratory of Molecular Pharmacology in NCI’s Center for Cancer Research, was published November 1 in Cancer Research.

PARP inhibitors have shown promising anticancer activity against breast and ovarian cancers in women with BRCA1 or BRCA2 gene mutations. The drugs were believed to block cancer cell growth by inhibiting the activity of PARP proteins, which help repair damaged DNA. Therefore, drugs with similar levels of PARP inhibition should have comparable anticancer effects. However, studies have indicated that treating cells with a PARP inhibitor causes more toxicity than would be achieved simply by loss of PARP activity, suggesting that these drugs may have a second mechanism of action.

The researchers showed that PARP inhibitors can also trap PARP proteins at sites of DNA damage, forming PARP-DNA complexes that are toxic to cells. The strength of the trapped PARP-DNA complexes correlated with a drug’s ability to kill cancer cells and varied widely between the three tested PARP inhibitors, which are currently being studied in clinical trials.

“While PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP,” said Dr. Pommier in a news release.

The new study also showed that PARP inhibition and PARP trapping are not directly related. Olaparib (AZD2281) was the most potent PARP inhibitor followed by veliparib (ABT-888) and then niraparib (MK-4827).

In contrast, cells treated with niraparib or olaparib formed the most potent PARP-DNA complexes. When combined with a DNA alkylating agent, niraparib and olaparib also were much more toxic to cancer cells than veliparib.

“Our findings suggest that clinicians who use PARP inhibitors in clinical trials should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used,” said first author Dr. Junko Murai, in a news release.

The researchers also investigated the effects of these PARP inhibitors on 30 cell lines that had different DNA repair genes inactivated. The results confirmed that cells without BRCA1 or BRCA2 function are more sensitive than normal cells to PARP inhibition. The study also revealed other genes not previously implicated in sensitizing cells to PARP inhibitors. These results may help determine which tumors are most likely to be susceptible to PARP inhibition.

This work was supported by NCI's Intramural Research Program.

Also in the News: Radium-223 Improves Survival in Men with Metastatic Prostate Cancer

Final data from a trial involving men with castrate-resistant prostate cancer that had spread to the bones showed that radium-223 (Alpharadin) improved overall survival by more than 3 months. Radium-223, part of a class of drugs called alpha-particle emitters, targets bone metastases.

The final results from the ALSYMPCA trial were presented October 28 at the American Society for Radiation Oncology annual meeting.

Overall survival in the final analysis of the trial was 14.9 months for men who received radium-223 compared with 11.3 months for men who received a placebo, a slight improvement over the findings of an interim analysis presented earlier this year.

Men treated with radium-223 also lived nearly 40 percent longer without having a skeletal-related event, such as a bone fracture or spinal cord compression, or the need for radiation therapy to treat symptomatic bone metastases.

Also in the Journals: Genetic Factors Linked to Lung Cancer in Asian Women Who Have Never Smoked

Researchers have identified three more regions of the genome that may play a role in the development of lung cancer in Asian women who have never smoked. One variant is on chromosome 10 and two are on chromosome 6. The study also confirmed previous reports linking regions of chromosomes 5, 3, and 17 to lung cancer in Asian women who have never smoked.

Women with one of the three newly identified genetic variants may be more susceptible to lung cancer caused by environmental exposures, including secondhand smoke, the researchers found, although this needs to be replicated in other studies. Contrary to previous research, this study found no evidence that a variant on chromosome 15 is associated with lung cancer in Asian women who have never smoked, which suggests that this variant may be smoking related.

The genome-wide association study included data from 14 studies and compared the genomes of 6,600 Asian women with lung cancer and 7,500 without lung cancer. Dr. Qing Lan of NCI’s Division of Cancer Epidemiology and Genetics and her colleagues published their findings November 11 in Nature Genetics.

This study was supported by the National Institutes of Health (ZIACP010121).

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