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January 8, 2013 • Volume 10 / Number 1


NCI Cancer Bulletin Suspends Publication

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Newly Discovered Gene Linked to Hepatitis C Virus Clearance, Treatment Response

Human liver cells treated to mimic infection with hepatitis C, showing the cell cytoplasm (green), nucleus (blue), and IFNL4 protein (red). Researchers have identified a genetic variant that is strongly associated with the ability to spontaneously clear infection with the hepatitis C virus (HCV) and with the response to treatment for chronic HCV infection, the leading cause of liver cancer in the United States.

And, in a surprising finding, the discovery of the variant led to the first identification of a previously unknown gene, IFNL4. The variant in this gene is directly responsible for the creation of a newly identified protein, called  Interferon Lambda 4 (IFNL4), from the interferon lambda family of proteins. Read more > >



  • Update

    • New Videos from NCI: "Understanding Your Cancer Prognosis"
  • Notes

    • In Memoriam: Dr. Elwood V. Jensen
    • NCI Central Institutional Review Board Receives Accreditation
    • Cyber-Seminar: Using State Cancer Profiles for Cancer Control
    • Summary of NCI Funding Patterns for FY2012 Available


    Dr. Barry Kramer

    NIH Research Radio: Dr. Barry Kramer on Cancer Screening

    The director of NCI's Division of Cancer Prevention and editor-in-chief of NCI's Physician Data Query Screening and Prevention Editorial Board talks with NIH Research Radio about cancer screening and the risks that are sometimes associated with it.

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    Type: (MP3) | Time 8:53 | Size: 10.1 MB | Read Transcipt

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

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Featured Article

Newly Discovered Gene Linked to Hepatitis C Virus Clearance, Treatment Response

Human liver cells treated to mimic infection with hepatitis C, showing the cell cytoplasm (green), nucleus (blue), and IFNL4 protein (red).Human liver cells treated to mimic infection with hepatitis C, showing the cell cytoplasm (green), nucleus (blue), and IFNL4 protein (red). The image shows cells from carriers of the favorable genetic variant (left) and the unfavorable variant (right). INFL4 is expressed only in carriers of the unfavorable variant.

Researchers have identified a genetic variant that is strongly associated with the ability to spontaneously clear infection with the hepatitis C virus (HCV) and with the response to treatment for chronic HCV infection, the leading cause of liver cancer in the United States.

And, in a surprising finding, the discovery of the variant led to the first identification of a previously unknown gene, IFNL4. The variant in this gene is directly responsible for the creation of a newly identified protein, called interferon lambda 4 (IFLN4), from the interferon lambda family of proteins.

Results from the study, led by NCI investigators, were published online January 6 in Nature Genetics.

Compared with a previously identified single nucleotide polymorphism (SNP) that is already being used in the clinic to guide treatment decisions, the new variant (called ss469415590) was found to be a stronger predictor of spontaneous infection clearance and treatment response in people of African ancestry. In people of Asian and European ancestry, the new variant provided the same predictive accuracy as the previously identified SNP (called rs12979860).

In the United States, nearly one-quarter of all chronic HCV infections are in African Americans. Overall, 80 percent of people infected with the virus will develop a chronic infection, and approximately 5 percent of those infections will develop into liver cancer.

The finding could quickly be translated into a new genetic test to help guide treatment, and it might eventually be the basis for new treatments for HCV, according to the study's co-lead investigator, Dr. Ludmila Prokunina-Olsson of the Laboratory of Translational Genomics in NCI's Division of Cancer Epidemiology and Genetics (DCEG).

And the finding could also lead to other discoveries. "It's a big deal to find a new interferon gene," Dr. Prokunina-Olsson said. "It raises the question of whether [the gene] might be important in other diseases as well."

No Variant, No Gene or Protein

The newly discovered gene is related to the interferon lambda family of genes, which contains three other members. These genes, which themselves were discovered just a decade ago, encode proteins that play a role in helping cells ward off some viruses.

It's a big deal to find a new interferon gene. It raises the question of whether [the gene] might be important in other diseases as well.

—Dr. Ludmila Prokunina-Olsson

The new variant has two forms, one in which a single nucleotide has been deleted and another in which this nucleotide is present. Only the deletion variant produces the IFNL4 protein, which appears to somehow hamper HCV clearance and response to standard HCV treatments, Dr. Prokunina-Olsson explained.

"If there is no genetic variant, there is no protein," she said. "It's a yes or no question."

Building on Prior Research

The study follows earlier genome-wide association studies (GWAS) that identified SNPs in a region of chromosome 19 near the IFNL3 gene (previously known as IL28B). These SNPs were strongly associated with HCV infection clearance and the response to treatment, which typically involves a combination of pegylated-interferon alfa and ribavirin, and, more recently, the addition of protease inhibitors.

For this new study, the research team wanted to examine more closely what was happening in this chromosomal region during an HCV assault, explained the study's other lead investigator, Dr. Thomas O'Brien of DCEG's Infections and Immunoepidemiology Branch.

"The original studies and follow-up studies didn't point to a specific functional variant or mechanism, which is not uncommon in GWAS," Dr. O'Brien noted.

Using RNA sequencing, the team analyzed the expression of all genes in fresh human liver cells that had been treated with synthetic RNA to mimic hepatitis C infection. Unlike other genome analysis techniques, RNA sequencing is not constrained by having to work from a known set of genes, Dr. Prokunina-Olsson said. "RNA sequencing shows you whatever is there, whether anybody knows about it or not," she explained.

The RNA sequencing analysis turned up expected activity among genes known to reside in this region of chromosome 19.

"Then we saw something that was not expected," Dr. Prokunina-Olsson continued. What they found were transcripts—RNA molecules—located near IFNL3 and in the area which was not known to contain any known or predicted genes.

"It took about 9 months to get from RNA sequencing to cloning and characterization of the new gene," she said. "It's very unusual to identify a totally new gene that was not even predicted to exist."

Using samples from two clinical trials involving patients with chronic HCV infection, the researchers found that, in African American patients, the deletion variant was much more strongly associated with poor treatment response than the previously identified SNP. They saw a similar pattern for spontaneous HCV clearance when they analyzed samples from two other studies. They also found that the deletion variant is far more common in individuals of African ancestry than in Europeans or Asians.

The finding presents a paradox, Dr. O'Brien continued. Interferons are so named because they interfere with infections. "But, in HCV infection, the IFNL4 protein appears to interfere with viral clearance," he said.

Implications for Patients and Researchers 

The impact of this finding could be far-reaching, noted Dr. Charles Rice, a leading HCV researcher at Rockefeller University in New York.

"Especially in terms of understanding more of the biology, more of the mechanisms, [the finding] has great promise," Dr. Rice said. The previous GWAS studies highlighted the importance of this chromosomal region to HCV clearance and treatment response. This new gene, Dr. Rice said, "looks like it may be a large part of the story …. It opens up a whole new series of investigations to figure out exactly what it's doing. It's really quite a breakthrough."

From a clinical perspective, developing a test to help predict the likelihood of treatment response could be a distinct possibility.

"If we want to use just one genetic test irrespective of a person's racial background, this new variant could be a universal clinical predictor for all patients because it appears to be more accurate than the current test in African American patients," Dr. O'Brien said.

The IFNL4 protein might also be a good target for therapy, the research team wrote. Because many individuals do not generate the IFNL4 protein at all, Dr. O'Brien noted, it does not appear to be essential and could potentially be inhibited therapeutically without adverse consequences.

Drs. O'Brien and Prokunina-Olsson are already studying whether the variant affects the response to an interferon-based treatment for advanced melanoma. They are also working with researchers at the National Institute of Allergy and Infectious Diseases to study whether the variant affects the response to new treatments that directly attack HCV.

Treatment for chronic HCV infection is rapidly shifting away from interferon-based therapies—which, although effective, can have particularly bad side effects—to newer antiviral treatments, Dr. Rice explained, so assessing how this new variant and the other SNPs affect response to these new therapies will be important.

Carmen Phillips

Cancer Research Highlights

Following Up on Genetic Study, Researchers Identify Potential Therapy for Bladder Cancer

In a recent study of bladder cancer, NCI researchers identified a genetic variant associated with a modest increase in risk of the disease. But, after investigating the biologic effects of the variant on cells, the researchers now believe that the variant could be a marker for identifying patients who may respond to an experimental therapy being tested in other cancers.

Up to 75 percent of patients of European descent with bladder cancer may have inherited the variant and could be candidates for the experimental treatment, the researchers reported last week in the Journal of the National Cancer Institute.

The variant occurs in a gene that encodes a protein found on the surface of cells. Many pancreatic and prostate tumors also highly express the protein, called the prostate stem cell antigen (PSCA). A monoclonal antibody called AGS-1C4D4 was developed to target the protein, and results from early-stage clinical trials in prostate cancer (here and here) have been reported.

"We believe the protein is also a promising potential therapeutic target for bladder cancer," said Dr. Ludmila Prokunina-Olsson of NCI's Division of Cancer Epidemiology and Genetics, who led the study. Whether the protein has a direct role in the disease is not yet clear, she added.

The variant (known as rs2294008) was identified during a genome-wide association study (GWAS) of bladder cancer in 2010. To follow up on this lead, the researchers created synthetic versions of the gene with and without the variant. Cells with the variant produced high levels of PSCA, whereas cells without the variant did not produce the protein. The researchers also observed this pattern in normal bladder and tumor tissues from patients.

The new results suggest that patients with bladder cancer who lack the variant would not benefit from therapy such as AGS-1C4D4 because their cells do not produce PSCA. Based on the findings, clinical trials are warranted to validate PSCA as a therapeutic target in bladder cancer and the variant as a predictive marker for treatment response, the study authors concluded.

The study provides "a good lesson that researchers need to understand more about the biology of the variants identified by GWAS," Dr. Prokunina-Olsson said. In this case, the variant was not strongly associated with bladder cancer risk, but further study revealed that it had strong biologic effects on expression of the protein.

"This is one of the first studies to show direct clinical implications of a genetic variant identified through genome-wide association studies for common cancers," Dr. Stephen Chanock, acting co-director for the NCI Center for Cancer Genomics, said in a statement.

Drug Combination Could Help Treat Deadly Form of Thyroid Cancer

New findings from cell and animal studies suggest that combination therapy with two anticancer drugs, paclitaxel and pazopanib, may help treat anaplastic thyroid cancer (ATC), a rare and deadly form of thyroid cancer. The preclinical study results, published January 2 in Science Translational Medicine, also point to a possible new treatment target for ATC.

"[This] seems like a potentially exciting combination for treating an incurable, aggressive malignancy … but human studies need to be done to see if it's effective," said Dr. Ann Gramza of NCI's Center for Cancer Research, who investigates new therapies for ATC but was not involved in the study. The median survival for ATC patients is only about 3 to 5 months, so "any treatment that has the potential to improve outcomes is welcome," Dr. Gramza added.

In a search for drug combinations that might be effective in treating ATC, Dr. Keith Bible of the Mayo Clinic in Rochester, MN, and his colleagues treated laboratory-grown ATC cells with paclitaxel alone and in combination with pazopanib.

"With combination treatment, we found that there was a delay in the process of cell division, which was associated with an enhancement of cell death. Cells treated with the combination could not successfully divide, and instead died," explained Dr. Bible. The drug combination also led to greater shrinkage of tumors formed by implanting ATC cells in mice than did either drug alone.

Further experiments showed that the combined effects of the two drugs are due at least in part to pazopanib's ability to block the activity of a regulatory protein called aurora A kinase, which is critical for cell division. This kinase appears to be a previously unrecognized target of pazopanib. The researchers also found that aurora A kinase messenger RNA and protein levels were significantly higher in tumor tissue from ATC patients than in normal thyroid tissue samples.

Thus, "aurora A looks to be an attractive candidate molecular target in ATC, especially when combined with drugs such as paclitaxel," Dr. Bible noted.

He and his colleagues have begun safety studies in patients with ATC in preparation for a randomized clinical trial to test whether paclitaxel plus pazopanib is more effective than paclitaxel alone when given with radiation therapy.

Although physicians view the prognosis for ATC patients as dire, "promising clinical and preclinical results are emerging that seem to be improving outcomes of patients with ATC," concluded Dr. Bible. "It is gratifying to see increasing efforts to try to improve therapy for these patients. Our ongoing clinical trial and this work represent but one such initiative."

Test May Inform Care of Women Infected with HPV

A new study has shown that women who test positive for human papilloma virus (HPV) but negative for the biomarker p16 do not need an immediate follow-up examination and can be safely rescreened for cervical cancer after 2 to 3 years. Dr. Guglielmo Ronco of the Centro per la Prevenzione Oncologica in Italy and his colleagues reported 3-year follow-up results of a substudy of the New Technologies for Cervical Cancer (NTCC) screening trial December 21 in Lancet Oncology.

Infection with high-risk HPV is the cause of almost all cervical cancers. Cervical cancer can be effectively prevented by treating precancerous cervical changes caused by HPV. Most infections with HPV resolve on their own within a few months or years, whereas cervical cancer can take 10 years or more to develop. Researchers are interested in finding screening tests to reduce unnecessary follow-up testing for women who would otherwise eventually clear the infection.

A group of women participating in the NTCC trial received HPV DNA tests; those who tested positive for high-risk HPV were referred for colposcopy, a procedure for detecting cervical precancer. They were also tested for the biomarker p16. A positive p16 test can indicate that cellular changes caused by HPV infection have occurred.

Previous results showed that a positive p16 test was sensitive and specific for patients with high-grade cervical intraepithelial neoplasia (CIN; classified as CIN2, CIN3, or higher), suggesting that women with a positive p16 test should be referred for colposcopy. But there were no prospective data that indicated how to manage women with a negative p16 test.

The researchers followed the study participants for 3 years after their initial screening to determine whether the screening interval for patients who were HPV positive but p16 negative could be safely extended. During the 3-year follow-up period, 9.7 percent of p16-positive women but only 1.7 percent of p16-negative women were found to have changes classified as CIN3 or higher. The relative risk of precancerous changes was also higher for p16-positive women between the ages of 35 and 60 compared with those aged 25 to 34 years.

The researchers suggested that using the p16 test to triage HPV-positive women can safely delay additional screening for p16-negative women for 2 to 3 years.

"Variations in health care settings and the availability of resources will also play a factor in determining screening intervals and how these tests may be used for HPV-positive women," said Dr. Nicolas Wentzensen of NCI's Division of Cancer Epidemiology and Genetics and the author of a commentary on the report. He noted that the study showed promising results, warranting further evaluation of p16 for triage of these women.

Other biomarkers for triage of HPV-positive women are being evaluated, but the study by Dr. Ronco and his colleagues is the first to look at 3-year follow-up data in a screening population.

Genetic Mutations Alone Do Not Dictate Cancer Cell Behavior

In laboratory experiments, researchers have found that colorectal tumor cells grown from a single cell behaved very differently, even though the cells were genetically identical. These findings, published last month in Science, suggest that cancer treatments may fail to eradicate tumors for reasons other than the standard rationale that cancer cells acquire more genetic changes as they multiply.

The researchers, led by Drs. Antonija Kreso and Catherine O'Brien of the University of Toronto, began by isolating single cells from 10 human colorectal cancers. They then transplanted each of these single cells into mice, where the single cells grew into tumors. The genomes of these tumor cells—including the mutations—were identical to that of the original founder cell. When the researchers transplanted cells from these tumors from one mouse to another, the genomes remained stable and did not acquire many new mutations, even when transplanted sequentially up to 5 times.

Despite having identical genomes, the cells within the new tumors behaved in different ways. Some cells reproduced consistently when transplanted from one mouse to another, while others lost their ability to reproduce over the course of one or several transplantations. And some cells seemed to regain their ability to reproduce after a period of dormancy—that is, they were not detected in the initial transplant but were detected in subsequent serial transplants, or they were detected in the initial transplant but not in one or more subsequent transplants and then became detectable again in later transplants. Genetic tests showed that the cells had not mutated enough to explain these different behaviors.

The researchers then tested whether the cells that behaved differently also responded differently to treatment with oxaliplatin (Eloxatin). Cancer cells from mice treated with the drug, when transplanted into new animals, produced tumors with a lower proportion of cells that had previously reproduced consistently and a higher proportion of cells that reproduced after a period of dormancy.

This finding suggests that "resting or slowly proliferating [colorectal cancer] cells can endure oxaliplatin treatment and reinitiate tumor growth," explained the authors.

"Our findings reveal another layer of complexity, beyond genetic diversity, that drives intratumoral heterogeneity of [colorectal cancer]," they added. The authors wrote that mechanisms underlying this nongenetic behavioral diversity could include interactions between tumor cells and their microenvironment, complex intracellular signaling networks, and epigenetic changes. Understanding how genetic changes and these nongenetic factors interact to confer treatment resistance should be a focus of future research, they concluded.

Also in the Journals: Substitute for Drug in Short Supply Found to Be Inferior

Several members of the Pediatric Hodgkin Lymphoma Consortium recently reported poorer outcomes among patients whose treatment regimens had been modified because of drug shortages. Since 2006, the group had been treating intermediate- and high-risk Hodgkin lymphoma patients with the Stanford V regimen, a combination of 7 drugs. When one of these drugs, mechlorethamine (Mustargen), became unavailable, the group substituted another drug, cyclophosphamide. Based on the available literature, the researchers believed the two drugs would be equally effective. The findings were reported last month in the New England Journal of Medicine.

But the researchers discovered that only 75 percent of patients who received cyclophosphamide were event-free after 2 years compared with 88 percent of those receiving mechlorethamine. Although no patients in the study have died, those who relapsed underwent treatments that carry greater risks of infertility and long-term toxic effects.

"Our results suggest that even promising substitute regimens should be examined carefully before adoption; what might appear to be a suitable alternative regimen may result in an inferior outcome—an intolerable situation for young people with curable disease," the authors concluded.

Further reading:

Also in the Journals: Video Explains Realities of CPR for Patients with Advanced Cancer

Cardiopulmonary resuscitation (CPR) does not revive most people with advanced cancer, and those who do survive often experience medical complications. A new study suggests that an educational video may help physicians communicate this information to patients in a meaningful way.

In the study, substantially more patients who watched a video depicting the realities of CPR were dissuaded from choosing the procedure than were patients who listened to a verbal explanation about the procedure's potential risks. The findings appeared last month in the Journal of Clinical Oncology.

The randomized trial included 150 patients with advanced cancer. Twenty percent of patients who watched the video wanted CPR compared with 48 percent of patients who received a verbal explanation. For patients still alive 6 and 8 weeks later, the percentages who wanted CPR remained about the same. A sample clip from the video can be viewed online.

Further reading: "Video Eases End-of-Life Care Discussions"


NIH Research Radio: Dr. Barry Kramer on Cancer Screening

Dr. Barry Kramer Dr. Barry Kramer

The director of NCI's Division of Cancer Prevention and editor-in-chief of NCI's Physician Data Query Screening and Prevention Editorial Board talks with NIH Research Radio about cancer screening and the risks that are sometimes associated with cancer screening.

To learn more about cancer screening, see the special issue on the Science behind Cancer Screening.

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Type: (MP3) | Time: 8:53 | Size: 10.1 MB | Read Transcript

Special Report

U.S. Cancer Deaths Continue Long-Term Decline

According to the latest national data, overall death rates from cancer declined from 2000 through 2009 in the United States, maintaining a trend seen since the early 1990s. Mortality fell for most cancer types, including the four most common types of cancer in the United States (lungcolon and rectum, breast, and prostate), although the trend varied by cancer type and across racial and ethnic groups. The complete "Annual Report to the Nation on the Status of Cancer, 1975–2009" appeared January 7 in the Journal of the National Cancer Institute.

The report also includes a special section on cancers associated with the human papillomavirus (HPV) that shows that, from 2008 through 2010, incidence rates rose for HPV-associated oropharyngeal, anal, and vulvar cancers. HPV vaccination rates in 2010 remained low among the target population of adolescent girls in the United States.

Chart showing that U.S. cancer death rates declined between 1975 and 2009.

As in past years, NCI, the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), and the North American Association of Central Cancer Registries (NAACCR) collaborated on the annual report. Cancer incidence data came from NCI's Surveillance, Epidemiology, and End Results (SEER) database and the CDC, with analyses of pooled data by NAACCR. Mortality data came from the CDC's National Center for Health Statistics.

Incidence Rates Vary, Death Rates Continue to Drop

Among men, the overall rate of cancer incidence fell by an average of 0.6 percent annually from 2000 through 2009. Cancer incidence rates were stable among women during the same time period and rose by 0.6 percent per year among children. (See the table.)

The declines in cancer mortality averaged 1.8 percent per year for men, 1.4 percent per year for women, and 1.8 percent for children (ages 0 to 14 years) from 2000 through 2009. During the same period, death rates among men fell for 10 of the 17 most common cancers and rose for three types of cancer. Death rates among women fell for 15 of the 18 most common cancers and also rose for three types of cancer.

"The continuing drop in cancer mortality over the past two decades is reason to cheer," said ACS Chief Executive Officer Dr. John R. Seffrin in a statement. "The challenge we now face is how to continue those gains in the face of new obstacles, like obesity and HPV infections. We must face these hurdles head on, without distraction, and without delay, by expanding access to proven strategies to prevent and control cancer."

HPV Vaccination Rates Low

The special section on HPV-related cancers showed that from 2000 through 2009, incidence rates for HPV-associated oropharyngeal cancer increased among white men and women, as did rates for anal cancer among white and black men and women. Incidence rates for cancer of the vulva also increased among white and black women. However, cervical cancer rates declined among all women except American Indian/Alaska Natives. In addition, cervical cancer incidence rates were higher among women living in lower-income areas.

The annual report also showed that, in 2010, fewer than half (48.7 percent) of girls ages 13 through 17 had received at least one dose of the HPV vaccine, and only 32 percent had received all three recommended doses, a rate that fell well short of the Department of Health and Human Services' Healthy People 2020 target of 80 percent. The rate is also much lower than vaccination rates reported in Canada (50 to 85 percent) and the United Kingdom and Australia (both higher than 70 percent).

Vaccination series completion rates were generally lower among certain populations, including girls living in the South, those living below the poverty level, and Hispanics.

"The influence that certain viral infections can have on cancer rates is significant and continued attention to the effect[s] of HPV infection, in particular, on cervical cancer rates is critical," said NCI Director Dr. Harold Varmus in a statement. "It is important, however, to note that the investments we have made in HPV research can only have the tremendous payoff of which they are capable if vaccination rates ... increase."

Cancer Incidence and Mortality Rates, 2000–2009

  • kidney
  • pancreas
  • liver
  • thyroid
  • melanoma
  • myeloma
  • prostate
  • lung
  • colorectal
  • stomach
  • larynx
  • thyroid
  • melanoma
  • kidney
  • pancreas
  • leukemia
  • liver
  • corpus and uterus
  • lung
  • colorectal
  • bladder
  • cervix
  • oral cavity and pharynx
  • ovary
  • stomach
  • melanoma
  • liver
  • pancreas
  • lung
  • prostate
  • colon and rectum
  • non-Hodgkin lymphoma
  • kidney
  • stomach
  • myeloma
  • oral cavity and pharynx
  • larynx
  • leukemia
  • pancreas
  • liver
  • corpus and uterus
  • lung
  • breast
  • colon and rectum
  • leukemia
  • non-Hodgkin lymphoma
  • brain and other nervous system
  • myeloma
  • kidney
  • stomach
  • cervix
  • bladder
  • esophagus
  • oral cavity and pharynx
  • ovary
  • gallbladder

Bill Robinson


Busting a Myth about How Chemotherapy Works

Dr. Anthony LetaiDr. Anthony Letai

Dr. Anthony Letai had just begun his first year of medical school when his mother was diagnosed with advanced colon cancer. As doctors began to treat her disease, she asked a question that her son is still trying to answer: How does chemotherapy work?

Chemotherapy kills rapidly dividing cells, her doctor had explained. At the time, Dr. Letai found this commonly held view to be "vaguely unsatisfying." As he learned more about cell biology and started a research lab at the Dana-Farber Cancer Institute, his dissatisfaction grew. The answer does not explain, for instance, why some cancers respond to chemotherapy and others do not.

"There are too many bad cases of cancer that seem to grow rapidly and resist chemotherapy, and too many that grow slowly and respond well to chemotherapy," Dr. Letai said recently. Although some textbooks and websites say that chemotherapy works by targeting rapidly dividing cells, in fact, there is limited evidence to support this idea.

"Chemotherapy has cured millions of people, but we don't know why it works," Dr. Letai said.

Profiling Cell Death

In recent years, however, an alternative explanation for how chemotherapy works has emerged from studies of mitochondria, the energy-producing organelles of cells. Mitochondria, it turns out, also play a role in a form of cell death known as apoptosis; this biologic process allows cells to "commit suicide" rather than to pass abnormalities on to the next generation of cells.

Cartoon illustrating the idea that some cancer cells are more ready to die when exposed to chemotherapy than others. (Illustration by Kris Sarosiek)Cartoon illustrating the idea that some cancer cells are more ready to die when exposed to chemotherapy than others. Cells near the cliff are "primed" for cell death, or apoptosis. (Illustration by Kris Sarosiek)

Building on this work, Dr. Letai and his colleagues recently demonstrated that some cancer cells are "more ready" to commit suicide through the apoptotic pathway than others, at least in the lab. Differences in this state of readiness—which the researchers call "priming"—may help explain the different responses patients have to chemotherapy, the researchers concluded.

They made the discovery by profiling stored cells from patients treated for acute myelogenous leukemia (AML). "We found that the patients who did best [after chemotherapy] were the ones with the most primed leukemia cells," Dr. Letai said. "These patients are the ones who stay in remission after chemotherapy."

Many patients with AML respond to chemotherapy and never relapse, whereas other patients do not respond at all or respond but eventually relapse. The new findings, reported in Cell, suggest that differences in priming may determine a patient's initial response to chemotherapy as well as the risk of relapse.

Expanding Knowledge

The Cell paper expands our knowledge about "the important role that mitochondria play in cell death," commented Dr. Douglas Green of St. Jude Children's Research Hospital, who studies apoptosis but was not involved in the research.

"Cancer cells show differential priming for death, and these differences correlate with the clinical response to conventional therapy," Dr. Green wrote in an e-mail. Further research could lead to new drugs that affect this pathway, although more work is needed to understand the components of the pathway, he added.

In the Cell study, Dr. Letai used an existing drug to increase the priming of cancer cells, which, in turn, made the cells more likely to die after exposure to chemotherapy. This finding suggests that it may be possible one day to identify patients whose cancer cells are not sensitive to chemotherapy and make the cells responsive.

"This study was a proof of concept," said Dr. Thanh-Trang Vo, the first author of the report. "A prospective study is necessary to see how well this profiling will help us to predict patient outcomes."

A New Test

Although AML was the focus of this work, the researchers previously had linked mitochondrial priming and sensitivity to chemotherapy in other cancers, including ovarian, multiple myeloma, and acute lymphocytic leukemia.

The innovation that made the current work possible was a test known as BH3 profiling. The test provides a measure of how close a cell is to the threshold of death based on the activity of proteins associated with the cell-death pathway. Cancer cells that are more primed than the patient's hematopoietic stem cells are most likely to respond well to chemotherapy, the researchers found.

Dr. Stephen Nimer, director of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, called the study "illuminating." "More research is needed to help us understand why the average patient's cancer can resist the basic chemotherapy approaches," he continued, "and this work is a step in that direction."

Follow-up studies to confirm the Cell results are under way, noted Dr. Nimer, who is also a scientific advisor to Gabrielle's Angel Foundation for Cancer Research. The foundation recently provided funding for this work to Dr. Letai and his collaborator, Dr. Scott Armstrong of the Memorial Sloan-Kettering Cancer Center.

Levels of Complexity 

For multicellular organisms, the cell-death pathway in mitochondria is a kind of failsafe measure, explained Dr. Vo, who is now a postdoctoral fellow at the University of California, Irvine. "If a cell is no longer fit for survival, it can activate the suicide pathway in mitochondria to prevent its own cellular dysfunction from harming the whole organism."

The biologic complexity of apoptosis is illustrated by the fact that no single protein could provide the readout the researchers needed, noted Dr. Tito Fojo of NCI's Center for Cancer Research, who studies drug resistance but had no role in the study.

"As researchers and clinicians, we would always like to measure just a single thing, such as a protein, and then select a drug for patients based on the test," he continued. "But this is not realistic because cells just aren't that simple."

How chemotherapy kills cancer cells is also complex, noted Dr. Fojo. The idea that these drugs kill rapidly dividing cells remains popular even though it has never been demonstrated, he added. "I hear people say this all the time, and I always ask them, 'Where are the data for this?'"

Current research shows that different sets of genes are associated with the proliferation of cancer cells and their sensitivity to chemotherapy.

"We know unequivocally that drug sensitivity has nothing to do with proliferation—these are two distinct properties of the cell," Dr. Fojo said. Support for this idea comes from the Cell study, which found no correlation between the rate of cell proliferation and sensitivity to chemotherapy among the samples studied.

Potential Clinical Applications

With his colleagues in the clinic, Dr. Letai is planning a study to see if BH3 profiling can prospectively identify patients with AML who need—or who do not need—a bone marrow transplant after their first remission. He believes the test might also help identify older patients who may not benefit from induction chemotherapy, which can be difficult for older patients.

Progress in the field will come as researchers understand and learn to manipulate the pro-apoptotic proteins of the BCL2 family, Dr. Green predicted. "We do not fundamentally understand how some of these proteins actually function, but we're getting there."

"Ultimately," he continued, "we will have drugs that directly activate these proteins, or that directly inhibit them, and these will be invaluable." In the meantime, Dr. Letai's lab will carry on its research, as summarized in a tagline on its website: "Working to restore the death sentence to cancer cells since 2004."

As for Dr. Letai, he pointed out that researchers can learn a lot from questions like the one his mother asked years ago. "The questions lay people ask can often harshly expose the limitations of our knowledge," he said.

Edward R. Winstead

A Closer Look

Communications This article is part of a series of stories related to cancer communications. You can read more articles in the series here.

Personal Stories, Evidence Drive Successful Antismoking Ad Campaign

Button from Tips from Former Smokers campaignThe campaign was "among the year's most memorable advertising, and perhaps among the best-ever work in its category," according to AdWeek.

AdWeek wasn't referring to the television commercial featuring a boy in a Darth Vader costume who starts the family's new car with "The Force." Nor were they talking about the latest hi-tech gadget being rolled out with a Super Bowl ad blitz.

The object of their professional acclaim was Tips from Former Smokers, the antismoking campaign developed by the Centers for Disease Control and Prevention (CDC). Tips was the first paid, national mass media campaign funded by the federal government urging adult smokers to quit. And, according to the data available thus far, the campaign was a rousing success.

When the ads ran last year, from March 19 to June 10, calls to NCI's smoking quitline, 1-800-QUIT-NOW, more than doubled, and visits to were five times the levels measured during the same 12-week period in 2011. Both resources were featured in the campaign, which placed ads on television, radio, the Internet, and billboards, as well as in print publications and movie theaters.

"The [campaign's] primary emphasis was on giving a voice to the 8 million people in the U.S. who are suffering from diseases caused by smoking, giving them an opportunity to tell their story," said Dr. Timothy McAfee, director of the CDC's Office on Smoking and Health (OSH), which spearheaded Tips.

The featured people, the provocative style, and the prominent placement of where to get help to quit did not happen by accident. They were supported by a foundation of research on how best to reach and make an impression on smokers.

"The view from within the tobacco control community is that this was a very well done and very evidence-based campaign," said Dr. Nancy Rigotti, who directs the Tobacco Research and Treatment Unit at Massachusetts General Hospital.

And, although researchers are still analyzing the Tips campaign's impact, based on the early indications of success, another round of ads is already being developed.

Real People, Real Consequences

Button from Tips from Former Smokers campaignSuccessful public health campaigns have employed various approaches and strategies, and the optimal approaches for an antismoking campaign have become pretty clear, explained Diane Beistle, who heads the OSH Health Communications Branch. Reviewing the published research "provides a pretty solid base for the efficacy of hard-hitting, emotionally resonant campaigns," she said.

For example, controlled studies of smokers have consistently shown that antitobacco ads that emphasize the harms of smoking in a way intended to generate an emotional response are most memorable and most likely to make smokers contemplate changing their behavior.

Those research findings are consistent with campaign effects in the real world. In New York, an antismoking mass media campaign that ran throughout much of the 2000s featured several gripping television ads—such as one of a woman lying in bed, struggling to breathe because of a smoking-related illness, as her young son gives her a glass of water. The campaign was credited with contributing to sharp declines in smoking in the state.

Everything You Always Wanted to Know about Media Campaigns Against Tobacco

Perhaps the most comprehensive resource on media campaigns against tobacco is The Role of the Media in Promoting and Reducing Tobacco Use.  

Chapter 11 and Chapter 12 of this NCI monograph provide thorough overviews of campaigns conducted in the United States and abroad. They also include detailed summaries of the studies conducted to assess their impact.

Both Tips and the New York campaigns used the results of the highly successful Australian campaign called Every Cigarette Is Doing You Damage, which began in 1997, to inform their ad development.

Although the U.S. and Australian campaigns featured some disturbing images (one of the Australian television ads, for example, showed smoking-induced plaque being squeezed out of the aorta of a deceased 32-year-old-smoker), just invoking fear isn't necessarily enough to ensure success, said Dr. Barbara Loken, a psychologist and professor of marketing at the University of Minnesota, whose research focuses on public health campaigns.

"Having a story line, a real narrative, is what really engages people," Dr. Loken said. To that end, Tips featured the stories of real people, such as Brandon, whose legs were amputated from the knees down because of a smoking-related condition called Buerger disease.

Although other elements, such as mortality statistics and advice from health care professionals, have a place in antitobacco campaigns, she continued, "having a real person whose life has been forever changed by smoking can be extremely effective."

Fringe Benefits

Studies have shown that the Australian and similar campaigns have also had important ancillary benefits. Although the campaigns were "almost entirely focused on making sure they resonated with adults, they also resonated with youth," noted Dr. McAfee.

Button from Tips from Former Smokers campaignWhen Australian researchers surveyed adolescents about their response to the Damage campaign, for instance, about one-quarter of teens who smoked regularly said the campaign convinced them to reduce the number of cigarettes they smoked.

The ancillary effects can be quite broad, stressed Dr. Melanie Wakefield of the Cancer Council Victoria, who has studied the impact of Damage and other antitobacco campaigns.

"To the extent that [the campaigns] reduce adult smoking, smoking becomes less normative in society as a whole, and that's good for youth," she said. "Second, these types of campaigns reduce smoking among adults who are parents, and we know that quitting in parents reduces the likelihood of their children taking up smoking."

The ability of these campaigns to "denormalize" smoking at the population level is very important, explained Dr. Kelly Blake, a program director in NCI's Health Communication and Informatics Research Branch. "Those effects are difficult, but not impossible, to isolate with well-designed studies," Dr. Blake said.

Taking Action and Measuring Success

Studies have shown that offering a way to act on the emotions aroused by an ad is critical to achieving the desired results, Dr. Rigotti explained.

Having a story line, a real narrative, is what really engages people.

—Dr. Barbara Loken

"Pairing a personal testimonial with actionable information … can really drive a response," she said.

In one study, for example, antismoking ads were run on TV and radio stations with predominantly African American audiences and directed viewers and listeners to their regional smoking quitline. As a result, the average number of weekly calls from African Americans to the quitline rose from fewer than 2 before the campaign to 86 during the campaign.

The challenge for all public health communication campaigns "is to show an effect on behavioral outcomes, in this case, smoking cessation," said Dr. Blake. "That requires an analysis over a longer period of time, but the interim and proxy measures [of the Tips campaign] are very promising markers of success."

Such an analysis is under way. CDC researchers are conducting a cohort study that includes thousands of smokers and nonsmokers, using pre- and post-campaign interviews to measure their awareness of the campaign and, for smokers, whether they have quit smoking or attempted to quit. They expect to report the preliminary results early next year.

A second round of the Tips campaign is also expected to roll out in 2013. According to Dr. McAfee, round two will be similar to the original campaign, featuring a new group of individuals who developed serious smoking-related illnesses.

With this next round, he added, the CDC hopes to build on the campaign's momentum and extend its impact, including more outreach to physicians.

"We think about 80 percent of smokers saw these ads during the 3 month campaign," Dr. McAfee said. "They can really provide a golden opportunity for physicians … to ask their patients who smoke about the ads and start a meaningful dialogue about quitting."

In the fall of 2013, meanwhile, the Food and Drug Administration (FDA) will roll out a national antitobacco campaign targeted at teens and young adults. According to Jennifer Haliski of the FDA's Center for Tobacco Products, the campaign, slated to run for 2 years, is a direct result of the expanded authority granted to the agency under the 2009 Family Smoking Prevention and Tobacco Control Act.

Carmen Phillips

Further reading: "Federal Campaign Seeks to Shrink Smoking Rates Further"

A Brief History of Antismoking Campaigns

Although Tips is the first federally financed national tobacco education ad campaign, some of the earliest mass media campaigns included public service announcements that ran in the late 1960s, when, under the Fairness Doctrine, a court ruling required stations to run the announcements for free to counter the frequent cigarette ads running on television and radio. Some announcements featured television and movie stars, such as the 1985 ad from the American Cancer Society that featured actor Yul Brynner and aired nationally shortly after Brynner died from lung cancer.

In the United States, successful state-wide campaigns have been conducted in a number of states, including California, Florida, Minnesota, and New York. California's long-running campaign, which began in 1989, highlighted the dangers of secondhand smoke and how to quit. It also featured messages against the tobacco industry. The ad campaign was one part of a larger state-wide tobacco control program that included a substantial increase in cigarette taxes. The California program has been credited with cutting smoking in California to record low rates; in 2010, only 11.9 percent of California adults smoked cigarettes, making California one of only two states to reach the federal Healthy People 2020 target of reducing adult smoking prevalence to 12 percent.  

In 2000, the American Legacy Foundation launched the Truth campaign, a paid, national antitobacco campaign targeting youth. Ads from the campaign used multiple messages and approaches, and many of the ads employed an anti-establishment, anti-industry tone. Over the time it ran, the Truth campaign was found to substantially reduce smoking among high school students.

Around the same time that the Truth campaign was launched, several large tobacco companies created their own ad campaigns encouraging youth not to smoke. Phillip Morris, for example, developed two national ad campaigns, one geared toward teens called Think. Don't Smoke., and one for parents called Talk. They'll Listen. Independent studies, however, found that the campaigns were at best ineffective and possibly counterproductive.

Featured Clinical Trial

Experimental Drug for Relapsed or Resistant Ovarian Cancer

Name of the Trial
Phase II Study of Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer (NCI-12-C-0191). See the protocol summary.

Dr. Christina Annunziata Dr. Christina Annunziata

Principal Investigator
Dr. Christina Annunziata, NCI Center for Cancer Research

Why This Trial Is Important
Epithelial ovarian cancer is the most common and most deadly type of gynecologic cancer. In 2012, more than 22,000 women were expected to receive a diagnosis of ovarian cancer, and approximately 15,500 were expected to die from the disease.

Most cases of ovarian cancer, along with the biologically similar fallopian tube and primary peritoneal cancers, initially respond to treatment with debulking surgery and combination chemotherapy. Some women cannot undergo surgery, however, and not all respond to chemotherapy. Furthermore, about 80 percent of those who do respond to initial treatment will eventually experience a relapse.

Although subsequent chemotherapy may help, the disease almost always returns and develops drug resistance. New treatments are desperately needed to help improve survival for women with these cancers.

An experimental drug called birinapant (TL32711) may be a new option for women with recurrent or treatment-resistant ovarian cancer. Birinapant acts as an antagonist of a family of proteins called inhibitors of apoptosis (IAPs). These proteins get their name from the role they play in regulating apoptosis, which is a type of programmed cell death that is normally initiated when cells become damaged or are no longer needed.

IAPs are an essential part of a cellular signaling pathway that is often activated in ovarian and related cancers. Preclinical studies by researchers at NCI suggest that birinapant may disrupt this signaling pathway, which ultimately causes ovarian cancer cells to undergo apoptosis.

In this phase II trial, women with metastatic or otherwise unresectable epithelial ovarian, fallopian tube, or primary peritoneal cancer that has recurred after, or has not responded to, previous therapies will receive birinapant intravenously once a week for the first 3 weeks of each 4-week cycle. Treatment will continue until disease progression or unacceptable toxicity occurs.

"Birinapant has shown very good activity in preclinical in vitro studies and mouse models of ovarian cancer cells," Dr. Annunziata said. "We've conducted in vitro studies in our lab of this drug both with and without TNF [tumor necrosis factor], and it looks like TNF increases the ability of birinapant to kill cancer cells that express the TNF receptor. Tumor necrosis factor levels have been found to be very high in some women with ovarian cancer, especially in ascites fluid. Birinapant seems to reprogram the TNF response from a cell stimulatory pathway to a cell death pathway."

Doctors want to determine the efficacy of birinapant in these cancers, as measured by overall response rate or stable disease lasting at least 6 months. They will also look at overall survival, toxicity, and the effect of birinapant on molecular markers, such as TNF, as secondary endpoints.

For More Information
See the lists of eligibility criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

An archive of "Featured Clinical Trial" columns is available at Update

New Videos from NCI: "Understanding Your Cancer Prognosis"

Screenshot of the Understanding Your Prognosis page

NCI has released a series of five videos for patients and their health care teams about how to understand and talk about cancer prognosis. The goal of the series is to improve how patients and their doctors talk about this difficult subject. The videos address questions patients may have such as, "What are my chances of recovery? Can I be cured? What is the likely course of my disease?" 

The main video, "Understanding Your Cancer Prognosis," features three patients with advanced cancer and their oncologist, Dr. Anthony L. Back of the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center. Dr. Back is an expert on doctor-patient communication.

Three more videos in the series take a closer look at how each patient approaches questions about his or her future. In "One Couple's Creative Response," an artist and her husband discover how to support each other's need for different kinds of information about her colorectal cancer prognosis. In "Diving Out of the Dark," a patient with non-Hodgkin lymphoma describes how he learned to ask for details about the likely outcome of his treatment. And "From Anger to Acceptance" features a patient with pancreatic cancer who lives each day with the attitude that no doctor can really tell her how long she has to live.

In the fifth video, "For Doctors, a Patient-Centered Approach," Dr. Back coaches other oncologists on how to discuss prognosis with their patients.

The videos and a related fact sheet are available on NCI's website and may be freely used for patient education, medical practice, or training.


In Memoriam: Dr. Elwood V. Jensen

Dr. Elwood V. JensenDr. Elwood V. Jensen

Dr. Elwood V. Jensen, who discovered that hormones bind to receptor proteins in cells, died December 16 at the age of 92. His research led to the development of treatments that enhance or inhibit the effects of hormones and, according to the Lasker Foundation, this work "transformed the treatment of breast cancer patients and saves or prolongs more than 100,000 lives annually."

Dr. Jensen graduated from Wittenberg College in 1940 and completed his Ph.D. in chemistry at the University of Chicago in 1944. Three years later, he joined the faculty of the University of Chicago as an assistant professor of surgery. At that time, researchers believed that hormones underwent a series of chemical reactions that led to the production of enzymes that affect cells.

In 1958, Dr. Jensen found that estrogen remains chemically unchanged once inside the cell. He also showed that estrogen binds to a hormone receptor that migrates to the nucleus and turns on specific genes.

By 1968, Dr. Jensen had developed a test to detect estrogen receptors in breast cancer cells. He and his colleagues found that about one-third of breast cancers have estrogen receptors and may depend on estrogen for growth. Testing the estrogen receptor-status of cancer cells is now standard for patients with breast cancer.

In the 1970s, Dr. Jensen and Dr. V. Craig Jordan showed that women with estrogen receptor-positive (ER-positive) breast cancer benefited from tamoxifen (Novaldex), a drug that binds to the estrogen receptor and inhibits the binding of estrogen. The Food and Drug Administration approved tamoxifen for the treatment of breast cancer in 1977 and for the prevention of breast cancer in 1990.

Dr. Jensen was an original member and later director of the University of Chicago's Ben May Department for Cancer Research. From 1983 to 1987, he served as medical director for the Ludwig Institute for Cancer Research in Zurich, Switzerland. Dr. Jensen also spent time at the National Institutes of Health, Cornell Medical College, the University of Hamburg, and the Karolinska Institute in Stockholm. In 2002, he joined the University of Cincinnati, where he was the George J. and Elizabeth Wile Chair in Cancer Research. He continued his research there until late 2011.

Dr. Jensen was elected to the U.S. National Academy of Sciences in 1974 and was a co-recipient of the Albert Lasker Basic Medical Research Award in 2004.

NCI Central Institutional Review Board Receives Accreditation

The Association for the Accreditation of Human Research Protection Programs (AAHRPP) recently awarded the NCI Central Institutional Review Board (CIRB) full accreditation. The CIRB provides a review process that can streamline local IRB reviews of national multicenter cancer treatment trials.

AAHRPP awards accreditation to organizations demonstrating the highest ethical standards in clinical research. Accreditation establishes that the NCI CIRB has robust review processes in place to ensure the safety and protection of people who participate in NCI-funded clinical studies.

The NCI CIRB is also changing to an independent review model. Under this model, research sites in different locations that have joined the NCI CIRB can rely solely on the CIRB to meet all IRB regulatory requirements, instead of undergoing a local IRB review.

A pilot study performed at 22 sites that conduct clinical research showed that participants enthusiastically supported the independent model. This model further reduces the administrative burden on local IRBs and investigators, shortens the time needed to start accruing participants, and, as a result, allows institutions to offer more clinical trials.

The change is part of the NCI national clinical trials network restructuring, which aims to reduce the length of time it takes to complete cancer clinical trials and bring new cancer treatments to patients. 

Cyber-Seminar: Using State Cancer Profiles for Cancer Control

Research to Reality banner

The January 15 NCI Research to Reality (R2R) cyber-seminar will discuss how to use State Cancer Profiles for cancer control research and practice to make a local impact.

The State Cancer Profiles website provides a system to identify the cancer burden in a standardized way to motivate action, integrate surveillance into cancer control planning, and expose health disparities. The website provides interactive graphics and maps that help researchers and practitioners decide where to focus cancer control efforts.

Antoinette Percy-Laurry of NCI’s Division of Cancer Control and Population Sciences will provide an overview of the tool, highlight recently added features and measures, and describe how the tool can be used.

Amanda Raftery, of the Indiana State Department of Health, and Wendy Noe, of the Susan G. Komen for the Cure Central Indiana Affiliate, will share their experiences using State Cancer Profiles to develop and implement cancer control plans and programs in Indiana.

For more information and to register, visit the R2R website, where you can join discussions. All R2R cyber-seminars are archived on the website about 1 week after the presentation. For more information on the cyber-seminar series, please e-mail

Summary of NCI Funding Patterns for FY2012 Available

In fiscal year 2012, NCI received 4,143 applications for R01 research grants, of which 618 (or approximately 15 percent) received funding. R01 grants are the most common type of NIH research grant.

Charts and a table summarizing the overall funding patterns for R01 and R21 grants by various categories of investigators are available online.

Chart showing success rate of NCI grant applications NCI FY2012: "Percentiled" R01 Applications, Awards and Success Rates