National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 24, 2009 • Volume 6 / Number 4

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Cancer Research Highlights

Possible Prostate Cancer Marker Found

Elevated concentration of a compound detected in the tumor tissue, blood, and urine of men with prostate cancer could indicate the aggressiveness of the disease, new research suggests. Levels of the compound, a metabolite called sarcosine, were elevated in men who had localized prostate cancers compared with benign adjacent tissue, and were even higher in metastatic disease. In addition, experiments with cultured cells indicated that sarcosine may actually contribute to the aggressiveness of prostate cancer, making the associated biochemical machinery a possible therapeutic target, the researchers reported in the February 12 Nature.

If confirmed, the discovery could lead to potentially noninvasive tests for identifying aggressive prostate tumors, perhaps by combining a panel of metabolites with other biomarkers. Physicians currently cannot predict which of these tumors are life threatening.

Sarcosine was identified during a systematic analysis of more than 1,100 metabolites in 262 clinical samples, including tissue, urine, and plasma from men without prostate cancer and those who had various stages of the disease. Dr. Christopher Beecher of the University of Michigan Medical School and his colleagues identified 87 metabolites that could distinguish prostate cancer from benign prostate tissue. Six of these, including sarcosine, had even higher levels in metastatic disease.

Additional experiments led by Dr. Arul Chinnaiyan, an NCI Early Detection Research Network investigator at the University of Michigan, implicated sarcosine in prostate cancer progression. Adding sarcosine to benign prostate cells caused the cells to become more invasive, while reducing sarcosine levels in cancer cells reduced their invasive capability and made them behave more like normal cells.

At a press briefing, Dr. Beecher stressed the importance of the unbiased nature of the study, noting that sarcosine had not been associated with prostate cancer previously. Dr. Chinnaiyan added that profiling all of the metabolites in cells, collectively called the metabolome, could complement large-scale investigations of genes and proteins. “This should give us a more holistic picture of the molecular alterations that occur in cancer,” he said.

Fertility Treatments Unlikely to Raise Ovarian Cancer Risk

During the last few decades, women taking fertility drugs in order to become pregnant have not had definitive evidence that such treatments would not increase their ovarian cancer risk. Now researchers from Denmark, who conducted the largest population-based cohort study thus far to address this question, have reported that fertility drugs do not increase a woman’s risk of ovarian cancer. The study, led by Dr. Allan Jensen of the Institute of Cancer Epidemiology in Copenhagen, appeared February 5 in the British Medical Journal.

The study involved 54,362 Danish women who were treated in fertility clinics between 1963 and 1998 and then followed for a median of 15 years; 156 of these women eventually developed invasive epithelial ovarian cancer.

Ovarian cancer risk was no greater for women who used any of four different groups of fertility drugs than for those who had not used these drugs. Of the ovarian cancer cases that did occur in this cohort, 58 percent were serous tumors—occurring in the outer lining of the ovary—and the incidence of this particular tumor type appears significantly higher only among women who had taken clomiphene, which was the most commonly used fertility drug. The authors noted that this association “may be real and important,” but they pointed out that long-term follow-up studies will be needed to confirm this finding. Also, because the usual peak age for ovarian cancer diagnosis is 63 and the average age of these women was only 47 by the end of the study, they will continue to monitor the cohort.

Nevertheless, “Some women who take fertility drugs will inevitably develop ovarian cancer by chance alone,” explained Dr. Penelope Webb in an accompanying editorial, “but current evidence suggests that women who use these drugs do not have an increased risk of developing ovarian cancer.”

Liver Cancer Incidence Continues Steep Climb

A new study by NCI researchers offers both good and bad news about the most common form of liver cancer, hepatocellular carcinoma (HCC). Between 1975 and 2005, the researchers found, HCC age-adjusted incidence rates tripled. However, between 1992 and 2005, HCC survival rates at 1 to 5 years all improved, including a near doubling in 1-year survival. The study was published online February 17 in the Journal of Clinical Oncology.

“Although the study could not determine why liver incidence rates are increasing, these trends may be partially attributable to an increase in chronic infections with hepatitis C virus, which together with hepatitis B virus is a major risk factor for liver cancer,” said the study’s lead author, Dr. Sean Altekruse from NCI’s Division of Cancer Control and Population Sciences.

To conduct the study, the research team analyzed data from NCI’s SEER Program, looking at 10-year birth cohorts from 1900 through the 1950s. Overall, HCC incidence rates increased from 1.6 cases per 100,000 people in 1975 to 4.9 per 100,000 in 2005. Consistent with previous findings, HCC is more often seen in men, for whom the incidence rate was three times higher than women during the study period.

From 1992 to 2005, the most significant increases in HCC incidence rates were in American Indians and Alaska Natives, followed by African Americans, whites, and Hispanics. While overall HCC incidence rates were highest among Asians and Pacific Islanders, these groups had a more modest increase in incidence.

The survival improvements may be due to tumors being diagnosed at earlier stages, but with 1-year overall survival rates still below 50 percent, there is significant room for further improvement, the study authors stressed.

“This report provides reason for optimism that, with more HCC screening of high-risk groups and treatment of low-stage disease, the burden of HCC can be lessened,” they wrote.

Compounds Found in Green Tea Block Bortezomib

Bortezomib (Velcade), a drug approved to treat multiple myeloma and being tested in clinical trials to treat several other cancer types, works by interfering with the activity of proteasomes, cellular structures that break down unneeded proteins. Based on laboratory data, scientists have proposed that compounds found in green tea, including epigallocatechin gallate (EGCG), may increase the effectiveness of bortezomib when given concurrently.

However, in a study published online February 3 in Blood, Dr. Axel Schönthal and colleagues from the University of Southern California found exactly the opposite—EGCG completely blocked the activity of bortezomib in multiple myeloma and glioblastoma cells lines, in tissue cultures from patients with multiple myeloma, and in mice implanted with multiple myeloma cells. In one set of experiments, the EGCG was supplied by a dietary supplement currently available over the counter. A second supplement containing complete green tea extract (GTE), as well as several other individual compounds found in green tea, also interfered with bortezomib-induced cell death.

The researchers found that EGCG directly bound to a chemical group (boronic acid) found in bortezomib. This prevented bortezomib from binding to and blocking the activity of the proteosomes, which would normally cause cell stress and cell death.

“We…would strongly urge patients undergoing [bortezomib] therapy to abstain from consuming green tea products,” stated the authors, “in particular those widely available, highly concentrated GTEs that are sold in liquid or capsule form.”

Gene Provides Target for Thyroid Cancer Treatment

Most targeted anticancer drugs work by decreasing the activity of a mutated gene or reducing the amount of a cell-signaling protein produced by such a gene. Researchers from the Mayo Clinic in Jacksonville, FL, have discovered that an experimental drug currently being tested in a clinical trial to treat anaplastic thyroid cancer (ATC) works in the opposite way, by activating a tumor-suppressor gene called RhoB, which inhibits the production of new cancer cells. Their results appeared online February 10 in Cancer Research.

The researchers tested an experimental drug called RS5444 (also called CS7017) in several thyroid cancer cell lines. They knew from previous work that this drug binds to a protein that can increase the expression of many genes.

Their experiments showed that after treatment with RS5444, this protein binds to and increases expression of RhoB, which then triggers increases in the protein p21, which in turn blocks cancer cell growth. This growth-blocking effect was dependent on RhoB.

Not all ATC cells are susceptible to the class of drugs that includes RS5444. To test whether RhoB could still be a target for therapy in such cells, the researchers treated them with a histone deacetylase inhibitor, which alters the structure of chromosomes and thereby changes the expression of certain genes. They found that altering the genetic structure in this way increased RhoB expression, which in turn increased p21, resulting in suppression of cancer cell growth.

RhoB is implicated as a critical signaling node that could be therapeutically targeted in ATC. Importantly, it is a target that can be up-regulated by multiple classes of drugs,” the authors concluded.

New ASCO/AUA Guideline for Prostate Cancer Prevention

Healthy men who have a prostate-specific antigen score of 3.0 or lower, who have no signs of prostate cancer, and who plan to be screened regularly for the disease should discuss with their physician whether to take 5-alpha reductase inhibitors (5-ARIs) to decrease their risk of developing prostate cancer. This is the recommendation of the American Society of Clinical Oncology (ASCO) and the American Urological Association, published today.

“We are not recommending that all men take 5-ARIs,” said Dr. Barry Kramer, associate director for disease prevention at NIH and co-chair of the panel that developed the guidelines on this topic, in an ASCO press release. “However, we would encourage men to begin a dialogue with their doctors to determine if they could benefit from taking 5-ARIs to reduce their prostate cancer risk.”

The panel’s recommendations are based on the results of clinical trials that have shown men who took this class of drugs, which include finasteride, for between 1 and 7 years had a 25-percent reduced risk of getting prostate cancer. Whether the drugs decrease mortality from the disease, however, is still not clear.

To assist patients with the discussion of 5-ARIs with their physician and their family, ASCO has published a decision aid tool that includes charts and diagrams explaining the risks and benefits of taking these drugs. The tool will be available on ASCO’s patient Web site. The full guidelines will be published in March in the Journal of Clinical Oncology and The Journal of Urology.

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