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

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BREAKING NEWS

FDA Bans Candy- and Fruit-Flavored Cigarettes

The FDA announced today that, effective immediately, cigarettes with certain flavors such as candy, fruit, and clove are now illegal in the United States. Flavored cigarettes are a gateway for many young people to become regular smokers, the agency said, and the ban, authorized by the new Family Smoking Prevention and Tobacco Control Act, aims to reduce the number of children who start smoking.

NEWS

Modified Chemo Regimen Effective in Advanced Ovarian Cancer

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up. The results were published online September 18 in The Lancet. Read more > >

COMMENTARY

Director's Update: Using ARRA Funds to Advance Cancer Research

As the fiscal year draws to a close September 30, a number of offices around NCI become especially busy places. Members of our staff who supervise budget issues, grant funding, program management, and contract administration put in long hours, making sure every dollar is appropriately allocated. In 2009, end-of-year responsibilities are even greater, as NCI also works to distribute $1.26 billion it received under the American Recovery and Reinvestment Act (ARRA). Read more > >

IN DEPTH

UPDATES

  • FDA Update

    • FDA Clears Test for Ovarian Cancer that Could Guide Surgical Decisions
    • Committees Recommend FDA Approve Cervarix and Gardasil

    Notes

    • Dr. Ming Lei Named Cancer Training Branch Chief
    • Dr. Louise Brinton Receives Lilienfeld Award
    • Webcast Registration Available for DCIS Conference

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

Modified Chemo Regimen Effective in Advanced Ovarian Cancer

Calendar

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up. The results were published online September 18 in The Lancet.

Although the toxicities of this dose-dense regimen were greater than they were in women who received the standard combination, survival benefits of this magnitude “have been rare in women with advanced ovarian cancer,” wrote Dr. Noriyuki Katsumata and colleagues from the Japanese Gynecologic Oncology Group (JGOG).

The results, explained Dr. Ted Trimble, from NCI’s Division of Cancer Treatment and Diagnosis, are consistent with what has been seen in breast cancer using a dose-dense chemotherapy regimen. The idea, he continued, is “to balance efficacy and toxicity by using a weekly schedule rather than every 3 weeks.”

Although the findings are important, “they won’t change practice overnight,” Dr. Trimble said. There are still several significant unknowns, including whether a lower dose of paclitaxel might be as effective but less toxic; the optimal timing of surgery; and where intraperitoneal chemotherapy fits into the treatment mix. The JGOG trial results, however, will influence the design of a number of phase III clinical trials, all of which include dose-dense chemotherapy, he added.

More than 630 women at 85 hospitals across Japan enrolled in the trial. Patients were randomly assigned to either of the two treatment groups. After 3 years of follow-up, women who received the dose-dense treatment had a median progression-free survival of 28 months, compared with 17 months for those who received the standard treatment.

Not enough time has passed to determine with statistical confidence whether the overall survival advantage will be maintained. However, in ovarian cancer, improvements in progression-free survival tend to predict overall survival, said Dr. Michael A. Bookman, chief of the Hematology/Oncology Section at the Arizona Cancer Center, in an accompanying editorial in The Lancet.

The dose-dense chemotherapy regimen used in the trial was also dose-intense, meaning the total dose of paclitaxel patients received was actually higher than in those who received standard treatment. This was associated with some toxic side effects that caused treatment delays and modifications and also led to patients receiving less caboplatin than intended. In fact, more than half of the women in the dose-dense group discontinued treatment early, and most of them did so because of the toxicity.

Although it’s possible that the dose intensity was responsible for the survival improvements, Dr. Bookman wrote, the more frequent, lower-dose treatment schedule is the most “plausible explanation.” As a result, “similar results might be achieved” with a lower dose, he concluded, “with improved tolerability.”

As for why the dose-dense approach is more effective than the standard approach, the Japanese researchers suggested that it hampers the formation of blood vessels that feed tumors. In animal model studies, dose-dense chemotherapy, like a similar treatment also under active investigation called metronomic chemotherapy, has been shown to have such an antiangiogenic effect. And in the JGOG trial, the researchers noted, tumor shrinkage following treatment did not differ between those receiving dose-dense chemotherapy and standard chemotherapy. This suggests that the dose-dense treatment “might promote tumor dormancy by maintaining tumor size and preventing outgrowth,” they wrote.

The U.S.-based Gynecologic Oncology Group is planning to launch a phase III clinical trial in advanced ovarian cancer combining the dose-dense approach with the targeted antiangiogenic drug bevacizumab (Avastin), said Dr. Ronald Alvarez, director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham. This should help to confirm the Japanese trial’s results.

In the meantime, “Given the potential toxicity, clinicians should discuss with their patients the risks versus the benefits of this approach in comparison with other treatment strategies,” Dr. Alvarez said, particularly with those patients who have advanced disease and whose tumors could not be mostly eradicated by surgery.

Carmen Phillips

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.

Director's Update

Using ARRA Funds to Advance Cancer Research

Dr. John E. Niederhuber Dr. John E. Niederhuber

As the fiscal year draws to a close September 30, a number of offices around NCI become especially busy places. Members of our staff who supervise budget issues, grant funding, program management, and contract administration put in long hours, making sure every dollar is appropriately allocated. In 2009, end-of-year responsibilities are even greater, as NCI also works to distribute the $1.26 billion it received under the American Recovery and Reinvestment Act (ARRA).

ARRA brought to the institute a large amount of money that must be used by our grantees in just 2 years, making it essential that almost all of the funding decisions for ARRA be completed in the 2009 fiscal year. These funds have made possible infusions of resources benefitting both individual investigators and large, team science projects. ARRA is, in fact, a once-in-a-lifetime opportunity for us to truly enhance the field of cancer research. There is also, I believe, an important message in the way the institute has chosen to use these vital resources. It is a story I was most proud to detail for the National Cancer Advisory Board last week.

Fifty-nine percent of NCI’s ARRA dollars are going to supplement existing grants or to fund new, competing grants. Individual investigators conducting hypothesis-driven science remain the backbone of NCI’s research portfolio, and for that reason, the support of investigators—established or new to the field—was the institute’s first priority. We modeled numerous scenarios to determine how many grants NCI could fund and whether to promise just 2 years of funding under ARRA or to extend the term of many grants to 4 or 5 years, committing appropriated dollars for the years of the grant after the ARRA support in years 1 and 2. By planning now for the “out years” after ARRA funds run out, we will be better able to maintain an acceptable level of support for laboratory and clinical scientists working in research universities across the United States and, hopefully, soften just a bit the landing, post-ARRA.

ARRA funds have also gone to education; to the pressing need of our universities and NCI-designated Cancer Centers, so they can continue to nurture great scientific minds. ARRA funds have gone toward programs to help new faculty members get started in their academic careers, to encourage some who may have gone in other scientific directions to return to biomedical research, to facilitate the hiring of summer students to work in labs around the country, and to develop a diverse cadre of new researchers.

Of the remaining ARRA funds, 39 percent are being dedicated to research and development contracts—opportunities for the academic community to participate in more directed, task-oriented research. To take just one example, NCI recently launched a Chemical Biology Consortium, a network of chemists that can be called on to collaborate in large or small teams, depending on the needs of an individual project, to help develop promising targeted therapies and more rapidly get those drugs into clinical trials. Members of the consortium, which will consist of eight universities and three commercial laboratories that were selected from more than 30 bidders, will be asked to carry out specific tasks with measurable outcomes and clear expectations for the project-specific dollars.

ARRA funds, in some cases supplementing appropriated dollars, have made possible a number of other important, directed initiatives.

ACTNOW, or Accelerating Clinical Trials of Novel Oncologic Pathways, will fund 37 early phase clinical trials of new treatment regimens. These awards will be contingent on obtaining Institutional Review Board approval for the trial and opening the trial to patient enrollment within 90 days of their award, with the target for completing enrollment in 2 years.

The Cancer Genome Atlas (TCGA), a project jointly led by NCI and the National Human Genome Research Institute, will expand its mission to identify all of the relevant genetic changes in cancer. In just 3 years, the TCGA pilot project has established state-of-the-art genome sequencing and analysis centers, which have facilitated groundbreaking genetic discoveries in glioblastoma multiforme (the most common and deadly form of brain cancer) and will soon publish important findings on ovarian cancer.

The cancer Biomedical Informatics Grid (caBIG) is moving forward with its ambitious plans to create a secure, nationwide infrastructure for the storage of patient data that will give scientists access to vast amounts of genomic information never before made widely accessible. Spurred by use of electronic cancer records, this resource has the potential to revolutionize the way clinician scientists conduct clinical trials.

The cancer Human Biobank (caHUB) is building a tissue acquisition, storage, and characterization center, which will operate as a centralized nonprofit public resource that will ensure the adequate and continuous supply of high quality, ethically obtained human biospecimens and associated data.

In the end, these initiatives and spending plans will truly matter when the new knowledge they generate reaches the patient’s bedside. Likewise, I believe it is our responsibility to convey the scientific excitement and promise that we see reflected in the activities ARRA has made possible. Each of the activities briefly described above is either being scaled up or started because of the availability of stimulus dollars. Without ARRA, many would have been delayed or only marginally supported. By wisely allocating all of the resources we are given, I believe we will hasten our successes. Cancer research is making progress. We know the White House and Congress are watching, as are those living with cancer and the people who love them. We realize all too well the need and the expectations of those who carry the burden of cancer.

Dr. John E. Niederhuber
Director, National Cancer Institute

Spotlight

Charting the Path from Infection to Cancer

Few people associate infection with cancer, but close to one-fifth of all cancers in the world are caused by infectious agents, including viruses, bacteria, and other microbes. In developing countries, the number is higher—about one in four—while in industrialized countries, such as the United States, it is about one in 12.

Infectious agents that can cause cancer are extremely common, infecting millions of people around the world. Yet it is rare and takes a long time for an infection to develop into cancer. “You need a lot of things to happen, or not happen, to get from an infection to cancer,” said Dr. Douglas R. Lowy, chief of NCI’s Laboratory of Cellular Oncology and a leader in the molecular biology of tumor viruses.

Helicobacter pylori is the strain of bacteria most widely known for its role in the development of stomach ulcers, but also as a significant risk factor for stomach cancer. Helicobacter pylori is the strain of bacteria most widely known for its role in the development of stomach ulcers, but also as a significant risk factor for stomach cancer.

The microbes responsible for most of the global burden of infection-associated cancer are: the bacterium Helicobacter pylori, which causes gastric cancer; cancer-causing strains of the human papillomavirus (HPV), which cause cervical cancer and other cancers; and the hepatitis B and C viruses, which cause liver cancer. These four microbes alone cause more than 15 percent of all cancers worldwide.

Other cancers known to be associated with infectious agents include leukemia and lymphoma; anal, penile, vaginal, and vulvar cancer; and tongue and throat cancers. Last week, researchers reported new evidence linking aggressive prostate tumors to a virus.

Role of the Immune System

Microbes can lead to cancer by a variety of mechanisms that are not yet fully understood, explained Dr. Allan Hildesheim, chief of NCI’s Infections and Immunoepidemiology Branch. The cancer-causing strains of HPV are known to disrupt the cell cycle and inactivate tumor suppressor proteins such as p53, which enables genetic damage to accumulate and, eventually, a cancer to form, he explained. H. pylori is believed to induce chronic inflammation, which can lead to atrophic gastritis and, over time, increases the risk of developing gastric cancer.

“In the case of the hepatitis B and C viruses, the problem may be less the infection itself than the immune system’s response to it. To fight off the infection, the immune system releases cytokines and other inflammatory proteins that can cause tissue damage,” said Dr. Hildesheim. “Over time this can lead to cirrhosis of the liver, which is a strong predisposing factor for liver cancer.”

Chronic suppression of the immune system is another cause of infection-associated cancer. People infected with the human immunodeficiency virus (HIV), which weakens the immune system, and organ-transplant recipients who take immunosuppressive medications to prevent transplant rejection are more vulnerable to infection-associated cancers than people whose immune systems function normally.

Similar Molecular Process

The molecular chain of events leading to an infection-induced cancer is similar to the process by which noninfectious cancers develop, said Dr. Patrick Moore, who directs the Molecular Virology Program at the University of Pittsburgh Cancer Institute. “The same tumor-suppressor signaling pathways that are mutated in noninfectious cancers are also inactivated by viruses,” said Dr. Moore. “Indeed, it was through research on viral causes of cancer that we learned much of what we now know about cancer-causing genes and tumor-suppressor signaling pathways.”

The two most recently discovered viruses believed to be associated with human cancer were both identified in Dr. Moore’s laboratory. In 1993, a group led by Dr. Moore and his wife Dr. Yuan Chang discovered the Kaposi sarcoma-associated herpesvirus, also called human herpesvirus-8 (HHV-8), which is the likely cause of Kaposi sarcoma. In 2008, the same team found compelling evidence that a newly discovered virus dubbed the Merkel cell polyomavirus causes most cases of Merkel cell carcinoma, an uncommon but lethal skin cancer.

Opportunities for Intervention

Cancers caused by infection “offer unique opportunities for intervention,” said Dr. Lowy. “We now have two vaccines—against hepatitis B and HPV—that can prevent cancer by preventing infection with the virus. Secondly, at least in theory, you can take aim at genes or proteins made by the infectious agent. The best example to date of this approach is antiretroviral therapy for HIV, which works because it has a much stronger effect on the genes and proteins made by the virus than on the body’s own genes and proteins.”

Many features of infection-associated cancers remain poorly understood. For example, for most of these cancers, only some cases are caused by infection. “Some liver cancers have nothing to do with hepatitis infection,” said Dr. Lowy. “Some oropharyngeal, vulvar, and penile cancers are caused by HPV infection, but others are not. On the other hand, virtually all cases of cervical cancer seem to be caused by HPV.”

Burkitt lymphoma in Africa is almost always caused by the Epstein-Barr virus (EBV), added Dr. Moore, whereas in the United States fewer than half the cases of this disease have a viral cause. “What we previously thought was a single cancer has been shown to be two or more types of cancer that look similar, some caused by a virus and some not.”

Some microbes, including EBV, cause different types of cancer in different parts of the world. “In southern China, nasopharyngeal cancer [a cancer of the throat] is the most common cancer manifestation of EBV infection,” said Dr. Hildesheim. “In sub-Saharan Africa, you rarely see nasopharyngeal carcinoma, but Burkitt lymphoma is relatively common.”

Genetic Susceptibility

The fact that most infections capable of causing cancer are very common, and yet only a small subset of those infected develop cancer, suggests that genetic and other factors may promote or protect against cancer in infected individuals, continued Dr. Hildesheim. “Those of us who study tumors caused by infectious agents have been a bit late joining the genetic revolution,” he said. “There is a tremendous amount we can learn.”

Recently he and his colleagues reported on the link between cervical cancer and single nucleotide polymorphisms (SNPs)—one-letter changes in the human genetic code—in genes involved in the immune response to infections and in the repair of DNA damage. They noted that some genetic polymorphisms are associated with increased risk of persistent HPV infection, a prerequisite for an HPV-induced cancer, while others are associated with the tendency for HPV-infected cells to progress to precancer or cervical cancer. Parallel studies have also confirmed findings by other researchers that certain variations in immune regulation genes known as HLA genes appear to affect cervical cancer risk.

“We are trying to understand how individual genetic factors may interact with HPV infection to predispose, or protect against, persistence of the infection or alter the ability to repair genetic damage caused by persistent HPV infection,” Dr. Hildesheim explained. “We and others are also studying whether differences in the genetics of HPV might explain why some infected individuals develop cancer while others do not and whether differences in the genetics of EBV may help to explain why the pattern of cancers associated with this virus is so different in different parts of the world.”

By better understanding cancer-causing infections, said Dr. Lowy, “the hope is that we will be able to prevent more cancers by preventing the infections that lead to the disease or by treating the infections before they develop into cancer.”

Eleanor Mayfield

The International Agency for Research on Cancer has classified the following infectious agents as carcinogenic or probably carcinogenic—that is, as causing or contributing to cancer development—in humans.

Infectious AgentAssociated Cancers
Viruses
Epstein-Barr virus (EBV)Burkitt lymphoma
Hodgkin lymphoma
Non-Hodgkin lymphoma
Nasopharyngeal carcinoma
NK/T-cell lymphoma
Hepatitis B virus (HBV)Hepatocellular carcinoma (a type of liver cancer)
Hepatitis C virus (HCV)Hepatocellular carcinoma
Non-Hodgkin lymphoma
Human papillomavirus types 16, 18, and others (HPV)Anal cancer
Cervical cancer
Oral cancer
Oropharyngeal cancer (cancer of the base of the tongue, tonsils, or upper throat)
Penile cancer
Vaginal cancer
Vulvar cancer
Human immunodeficiency virus 1 (HIV 1)A variety of immunosuppression-related cancers
Anal cancer
Cervical cancer
Conjunctiva cancer (in the eye)
Hodgkin lymphoma
Kaposi sarcoma
Non-Hodgkin lymphoma
Human T-cell lymphotropic virus 1 (HTLV 1)Adult T-cell leukemia/lymphoma
Lymphoma
Kaposi sarcoma herpesvirus/ human herpesvirus 8 (KSHV/HHV 8)Kaposi sarcoma
Primary effusion lymphoma
Other infectious agents
Helicobacter pylori (bacterium)Gastric (stomach) cancer
Liver flukes (parasite)Cholangiocarcinoma (a type of liver cancer)
Schistosomes (parasite)Bladder cancer

A Closer Look

Harnessing the Biological Activity of Natural Products

Many herbs, dietary supplements, and even vitamins are suspected of interfering with chemotherapy and radiation therapy, and doctors now routinely advise patients who are undergoing cancer treatment to avoid taking these products.

At the same time, cancer researchers have been intrigued by the potent and beneficial biological activity shown by some natural products and are testing ways to incorporate them into standard and experimental treatment regimens, both to enhance the anticancer effects of therapy and reduce the side effects.

Natural products, including foods like grapefruit juice, are being studied for their ability to enhance cancer treatment Natural products, including foods like grapefruit juice, are being studied for their ability to enhance cancer treatment

A Treatment More than 1,700 Years in the Making

Dr. Yung-Chi Cheng, Henry Bronson Professor of Pharmacology at the Yale University School of Medicine, is interested in herbal compounds that are used in traditional Chinese medicine (TCM). Among other projects, his laboratory has reformulated a Chinese herbal mixture that has been used in TCM for more than 1,700 years to treat gastrointestinal problems, including diarrhea, nausea, and vomiting.

This reformulation, called PHY906, was originally tested to lessen the gastrointestinal side effects of chemotherapy, and, in a small, early clinical study, the compound successfully reduced side effects in patients with colon cancer who received the drugs irinotecan and 5-fluorouracil.

Dr. Cheng and his colleagues also observed a synergistic anticancer effect when the compound was given in combination with irinotecan in animal studies—a result that was surprising, said Dr. Cheng.

PHY906 alone had no effect on these tumors, but irinotecan plus PHY906 had greater antitumor activity than irinotecan alone. Now PHY906 is being tested for potential anticancer activity in combination with traditional chemotherapy drugs in three clinical trials. (The trial for colorectal cancer is still accruing patients.)

In tandem, to understand the molecular mechanisms behind the combination’s effects, Dr. Cheng and colleagues are collaborating with Dr. Francesco Marincola, chief of the Infectious Disease and Immunogenetics Section at the NIH Clinical Center, who is using mouse models to measure changes in gene expression after PHY906 and chemotherapy drug administration.

Their preliminary results indicate that “when PHY906 is combined with chemotherapy, this causes a potent inflammatory response, similar to that observed during the rejection of cancer cells during immunotherapy,” said Dr. Marincola. “PHY906 may enhance the effects of chemotherapy by adding an anticancer immune response.”

From Supermarket to Clinic

Herbal medicines with a long history of use are one type of product being examined for potential uses in modern medicine. But some food products consumed in a normal diet can also affect the workings of the body at the molecular level. One of these foods—grapefruit juice—is now being studied for novel applications in cancer treatment.

Though widely consumed for its high levels of vitamin C and potassium, grapefruit juice is far from an innocuous drink in the eyes of doctors. It contains a class of compounds called furanocoumarins, which block an enzyme found in the digestive system and liver called CYP3A4.

As a result, certain drugs that are normally metabolized by the enzyme stay in the body longer and at higher concentrations if they are taken with grapefruit juice. This can lead to overdoses of some blood-pressure medications, antidepressants, and antiretroviral drugs for HIV, for example.

Grapefruit juice’s ability to slow the metabolism of certain drugs, however, caught the eye of researchers at the University of Chicago, who were interested in testing the immunosuppressant drug rapamycin as an anticancer agent.

Rapamycin has extremely poor bioavailability—when taken orally, less than 15 percent of the drug is absorbed into the body. As a result, “We had to use high doses of rapamycin to achieve the blood levels that we wanted,” explained Dr. Ezra Cohen from the University of Chicago Medical Center, and the high doses led to unwanted toxicities, such as severe diarrhea caused by surplus rapamycin leaving the intestines.

Looking for a way to give rapamycin more time to reach the bloodstream, Dr. Cohen and his colleagues hit on the idea of administering the drug with grapefruit juice.

In a promising phase I trial presented at this year’s meeting of the American Association for Cancer Research, the combination was given to 28 patients with advanced, incurable solid tumors, 7 of who experienced stable disease and one who had a partial response to treatment that has lasted for more than a year.

An added benefit was that co-administration of grapefruit juice allowed for once-weekly doses of rapamycin instead of the traditional once-daily doses, greatly reducing the cost of the therapy.

“There are a lot of [anticancer] drugs that I think would be amenable to this type of approach, because they have poor oral bioavailability, have side effects related to that poor absorption, and are expensive,” said Dr. Cohen. He strongly cautioned that patients should not mix grapefruit juice and chemotherapy outside of clinical trials, as the safety of the combination is still being explored.

—Sharon Reynolds

Profiles in Cancer Research

Dr. Jun S. Wei

Dr. Jun Wei Staff Scientist, Oncogenomics Section
Pediatric Oncology Branch, NCI's Center for Cancer Research

Dr. Jun Wei’s journey into cancer research began in the 1980s in Shanghai—a cosmopolitan cultural center of China, the first country in history to reach a billion people, and a society just beginning to emerge from the Cultural Revolution. Jun Wei, teenaged son of a physician and a chemical engineer, was thinking about science.

“The idea of our generation was if you have talent or potential you study science or engineering, because not everyone can do that,” he explained. “You are encouraged from the time you’re very young.

“Coming to the United States for college was not that common in the ‘80s,” he said, though some of the practical and financial hurdles were lowered because his uncle’s family was already well established in Houston. One of his uncle’s daughters, Victoria, was around Jun’s age and still in college. The two became very close, and his cousin helped him to assimilate into the new culture as Jun began his studies in biology at the University of Houston.

After becoming more fluent in English and working hard in college, he won a scholarship in 1992 to the Baylor College of Medicine. “In the early 1990s I saw that ‘molecular’ was becoming a buzzword,” recalled Dr. Wei. “I can’t say at that time that I had ‘the big picture’ of a career in mind, but looking back, getting into molecular biology was a good choice.”

For someone who would go on to become a leader in a diverse, active genomics laboratory, the cardiovascular sciences program in the DeBakey Heart Center proved to be the ideal training ground. During the mid-1990s he studied molecular and cell biology, while at the same time becoming fascinated by the emergence and promise of molecular tools like DNA microarrays.

  

Dr. Jun Wei describes his work using genetic research to predict disease outcomes in children with neuroblastoma, a form of cancer that occurs most often in infants under the age of 1.

Dr. Wei’s graduate school training in the 1990s coincided with a dramatic change in the potential of molecular biology. In biomedical research, a genome-wide hunt for disease-causing genes was afoot, even if searching for those genes remained difficult at the molecular level. Current NIH Director Dr. Francis Collins was at the helm of the National Human Genome Research Institute (NHGRI) at the time, driving toward the goal of decoding the human genome. Microarray technology was just about to take off, and Dr. Paul Meltzer’s laboratory was one of only a few at NIH (and the world) using that approach to study cancer genetics.

So in 1999, Ph.D. in hand, Dr. Wei answered an NHGRI ad in the British journal Nature for a molecular biologist to study Ewing sarcoma, an uncommon pediatric bone and soft tissue tumor. The senior research fellow he would be working with was Dr. Javed Khan, a Cambridge-trained physician-scientist who had been doing early work at the Sanger Institute in cytogenetics, who began to tutor the junior postdoc in the budding art and science of using microarrays.

The connection would prove to be symbiotic, as Dr. Khan quickly realized. “Jun had an impressive command of a wide range of cell and molecular biology techniques,” he recalled.

“You have to remember,” said Dr. Wei, “in those days, fabrication of microarrays was not yet perfected. We had to basically build them from scratch.” This was a daunting, painstaking process, sometimes requiring hundreds of steps, reliant on judgment, keen observation, and a deft manual touch for manipulating a miniature world that was sensitive to temperature, humidity, and other vagaries of the laboratory environment. “Everything you can imagine could and often did go wrong,” said Dr. Wei.

“But Jun was quite amazing, very adept working in that world,” countered Dr. Khan, who persuaded his lab partner to come with him 2 years later when he moved to NCI to head the Oncogenomics Section of the Pediatric Oncology Branch in the Center for Cancer Research.

Genomics in the Trenches

For nearly a decade now they have been partners and collaborators. Dr. Wei runs Dr. Khan’s lab, one of only a few in the branch using these advanced oncogenomic approaches to study cancers like rhabdomyosarcoma and neuroblastoma.

“You could see that genomics was just taking off when we first started working together, and it was really exciting to get in at that early stage,” said Dr. Wei. “At the time we were actually printing our own DNA microarrays, using what was then cutting-edge technology, but which looks very crude in hindsight.” DNA microarrays have since become one of the most important and widely used genomic tools for cancer research, allowing researchers to look for DNA changes by matching a particular specimen of tissue from a patient to features printed on the chip, which can be as high as tens of thousands or even millions, in one experiment.

“Oncogenomics is a marriage between molecular biology and genetics,” explained Dr. Wei. “Genomic studies systematically hunt for inherited genetic differences between people who have and those who do not have a specific disease. But do these differences cause the disease? Genomic studies only narrow the search to pursue that question.”

Drs. Khan, Wei, and their colleagues take the search further, trying to find out how DNA alterations of all sorts come to matter in cancer. “DNA is a very dynamic and complex system, subject to mutation every time cells divide,” Dr. Wei said. In the lab they are now sequencing the whole tumor genome using next-generation sequencing technologies and comparing the changes with those found in normal tissue taken from the same patient. The resulting molecular profiles, said Dr. Wei, are becoming a “game-changing way” to diagnose cancer, to predict a patient’s response to a particular therapy and his or her outcome, and even to personalize treatment for individual patients.

Their lab has been pioneering this approach since 2001, mastering and enhancing microarray technologies and creating new tools such as artificial neural networks—computer models that can adapt to input by changing and learning like the human brain. Their ultimate target is to discover the “drivers,” the critical genes that are causing cancers and which might also become targets for novel therapies.

From Bench to Bedside

Clinical relevance is the key. “You can go fishing for mutations associated with disease,” explained Dr. Wei, or “you can put a suspicious mutation into a cell and run a controlled experiment to see if it causes the disease.”

Those cell and animal experiments are Dr. Wei’s playing field. Reflecting back on the thousands of hours he has spent in the lab, honing his skills and his instincts as a molecular and cell biologist, Dr. Wei recalls the time he spent with his cousin Victoria studying at the University of Houston library until closing time, where he deciphered medical and biology textbooks and scientific papers with his newly acquired English—something Dr. Wei described as “not so much fun.” But the effort has no doubt helped him develop the sympathetic perspective to better supervise, train, and mentor postdocs in the lab.

The new generation of researchers will have to master a lot of new tools, while trying not to lose sight of what makes this kind of molecular science “biology”—the study of living things, he said.

“Picking up the newest technology, that’s not hard,” he explained. “The challenge is: How do you use this new technology in an innovative way? Everybody can learn to use tools, but how do you use the tools to make a beautiful piece of work?”

Dr. Wei is clearly driven by his lab’s mission. “These childhood diseases can be heartbreaking. Because many of them involve developmental genes, they form in a way that makes it impossible to screen and difficult to detect at early, treatable stages,” he explained. “By the time we get most of these kids into treatment, only 30 percent of them are likely to survive.”

You can hear the scientist explaining, but also an echo of a father who empathizes with the parents of children who have cancer. Dr. Wei paused, silent, before pointing with pride to an intricate 3-D collage his 7-year-old daughter, Esther, created that hangs on his office wall.

“The trick is to make your research into your artwork that would be beneficial to those kids with cancer,” he said.

—Addison Greenwood

Featured Clinical Trial

Comparing Drug Regimens for Diffuse Large B-cell Lymphoma

Name of the Trial
Phase III Randomized Study of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) Versus Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (EPOCH-R) in Patients with Previously Untreated De Novo Diffuse Large B-Cell Non-Hodgkin Lymphoma (CALGB-50303). See the protocol summary.

Dr. Wyndham Wilson Dr. Wyndham Wilson

Principal Investigators
Dr. Wyndham Wilson, NCI Center for Cancer Research; Dr. Andrew D. Zelenetz, Cancer and Leukemia Group B

Why This Trial Is Important
Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. Research by NCI scientists on the genetics of DLBCL has revealed that there may be three distinct subtypes of this disease, each characterized by a different pattern of gene expression.

Standard treatment for DLBCL is R-CHOP, which consists of a chemotherapy drug combination known as CHOP along with the antibody rituximab. Treatment with R-CHOP succeeds in curing more than 50 percent of DLBCL patients; however, many patients still experience progressive or recurrent disease and ultimately die from their cancer.

Another form of combination chemotherapy for aggressive lymphomas, called EPOCH, has been developed by NCI researchers. EPOCH contains the same drugs as CHOP, but it also includes the drug etoposide. Similar to CHOP, EPOCH can be paired with rituximab (EPOCH-R). However, several components of EPOCH-R are given as a continuous infusion over a 4-day period, allowing their doses to be adjusted to achieve optimum concentrations in the blood of each patient. The administration of R-CHOP does not allow for such adjustments.

Some evidence suggests that the benefit of rituximab varies with DLBCL subtype. In addition, other research suggests that EPOCH-R may be effective against subtypes of DLBCL that are resistant to R-CHOP. Consequently, researchers want to know if different therapeutic regimens can increase the cure rates for patients with different DLBCL subtypes.

In this trial, patients with previously untreated DLBCL will be randomly assigned to receive either R-CHOP or EPOCH-R for 6 to 8 cycles. Researchers will monitor the patients for event-free survival (the length of time after the start of treatment until the occurrence of a disease-related event, including progression, relapse, or death), response rate, and overall survival, and they will try to correlate these clinical outcomes with the molecular features of each patient’s cancer, as determined by gene expression profiling.

“There are two important endpoints for this trial,” said Dr. Wilson. “First, can EPOCH-R produce better clinical outcomes than R-CHOP for patients with DLBCL? Second, can we use gene expression profiling to determine prognostic molecular characteristics that will tell us which patients benefit most from these different regimens?”

For More Information
See the lists of entry criteria and trial contact information or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/ft-all-featured-trials.

FDA Update

FDA Clears Test for Ovarian Cancer that Could Guide Surgical Decisions

Last week the FDA cleared the use of a blood test that can help determine whether a pelvic mass may be cancerous for women who have already been selected for surgery. When combined with other types of information, the test, called OVA1, can help patients and their health care providers decide which type of surgeries should be done and by whom, the FDA said in a statement.

Studies have shown that women with ovarian cancer survive longer when their surgeries are performed by gynecologic oncologists rather than by general gynecologists or surgeons. The American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists have recommended that women be referred to a gynecological oncologist when specific signs of cancer are present.

OVA1 works by testing the blood levels of five proteins that vary in the presence of cancer. Based on these levels, the test produces an overall score between 0 and 10 to indicate the likelihood that the pelvic mass is benign or malignant. How the test is interpreted depends on a woman’s menopausal status.

The FDA decision was based on a study of 516 patients that compared OVA1 results with biopsy results. When combined with presurgical information, such as radiography and other laboratory tests, results from OVA1 tests identified additional patients who might benefit from an oncology referral who had not been identified using presurgical information alone, the agency said.

“Tests such as OVA1 personalize and improve public health by providing patients and health care providers with more information to support medical decisions that impact survival rates and reduce surgical complications,” Dr. Jeffrey Shuren, acting director of the FDA’s Center for Devices and Radiological Health, said in the statement.

Committees Recommend FDA Approve Cervarix and Gardasil

Last week, the FDA received recommendations to approve two vaccines against the human papillomavirus (HPV) that causes cervical cancer.

The vaccine Cervarix is licensed in nearly 100 countries worldwide and approved by the World Health Organization, but it has been awaiting FDA approval since its initial application in 2007 raised concerns about possible side effects. Though structured as a bivalent vaccine to protect only against HPV types 16 and 18, Cervarix has been shown in a recent trial to provide cross-protection against three other HPV types and may also produce a higher degree of protection against precancerous lesions known as grade II cervical intraepithelial neoplasias (CIN2+) than the vaccine Gardasil.

Gardasil has been approved for cervical cancer protection in females aged 9 to 26 since 2006, and targets two additional HPV types that are linked to genital warts, which can occur in males, as well. A second expert committee recommended FDA approval be extended to males in that same age group. The clinical trials on which the committee based its recommendation showed that Gardasil was 89 percent effective in preventing genital warts and had no side effects, though it was less effective in those who had already been exposed to HPV.

Notes

Dr. Ming Lei Named Cancer Training Branch Chief

Dr. Ming Lei Dr. Ming Lei

Dr. Ming Lei has been appointed chief of the Cancer Training Branch in NCI’s Center for Cancer Training. The Cancer Training Branch develops, administers, and manages the extramural, grant-supported research training and health professional career development programs at NCI.

Dr. Lei received his Ph.D. in molecular biology from Cornell University. He was an associate professor in the Department of Microbiology and Molecular Genetics at the Medical College of Wisconsin, where his research laboratory studied regulation of DNA replication and chromatin assembly. Dr. Lei served as a program director and cluster leader at the National Science Foundation before joining NCI in 2008 as a program director in the Division of Cancer Biology.

As chief of the Cancer Training Branch, Dr. Lei will oversee national strategies for training and career development of basic, clinical, and population-focused cancer scientists, and fostering education, outreach, and curriculum development activities in fields that support cancer research.

Dr. Louise Brinton Receives Lilienfeld Award

Dr. Louise Brinton Dr. Louise Brinton

In recognition of her outstanding career in cancer epidemiology, Dr. Louise A. Brinton of NCI’s Division of Cancer Epidemiology and Genetics received the 2009 Abraham Lilienfeld Award at the American College of Epidemiology’s annual meeting on September 12–15 in Silver Spring, MD.

Dr. Brinton’s current research focuses on the application of biomarkers of genetic susceptibility, endogenous hormones, and risk factors for breast and gynecologic cancers.

Upon receiving the award, she gave the Lilienfeld Award Lecture, reflecting on the uniqueness of epidemiology as a science and the ways in which the discipline has evolved. She emphasized the critical importance of training the next generation of epidemiologists and knowing how to conduct field work.

Webcast Registration Available for DCIS Conference

DCIS Conference logo

Beginning today, NCI and NIH’s Office of Medical Applications of Research are convening a 3-day, state-of-the-science conference on ductal carcinoma in situ (DCIS) at the Natcher Conference Center on the NIH campus. Participants who are unable to attend the conference in person may sign up online to view the live Webcast and receive the final conference statement. 

The panel’s draft statement will be posted on the Consensus Development Program Web site for public download on the evening of September 24. Final conference statements are usually available online approximately 6 weeks after a conference, and printed copies are typically mailed approximately 4 months later.