Using the anti-EGFR therapy cetuximab (Erbitux) to treat patients with metastatic colorectal cancer who have the normal form of the KRAS gene—and not the mutant form—would save more than $600 million annually, according to study results presented January 14 at the Gastrointestinal Cancers Symposium in San Francisco. Read more > > 6
A meta-analysis clarifies the degree of risk reduction with salpingo-oophorectomy
A meta-analysis shows that tandem autologous hematopoietic stem cell transplant carries risks without a survival benefit
With similar treatment, African American women have similar survival outcomes as women of other races
A new technique can identify an underappreciated class of mutations in cancer
One week ago today the country inaugurated Barack Obama as our new president, an occasion accompanied by the excitement associated with such a historic election. There are great expectations that the new president will make significant changes—changes that will touch nearly every aspect of our daily lives, patient care and cancer research included. As a citizen and as NCI director, I share those expectations, the anticipation, and excitement of hope. The hope for an adjustment to our country's compass toward the renewed investment in science, in the creation of new knowledge, and in the education of our talented young people. Read more > > 11
An NCI epidemiologist discusses the goals and implications of the 2008 Physical Activity Guidelines for Americans. Read more > > 12
has long been an indispensable model organism for genetics research, but its use in cancer genetics has been fairly limited, until recently
Fluorescent proteins, which have illuminated aspects of biology that were long hidden, could enter the clinic
What dosage of the angiogenesis inhibitor cediranib is safe for pediatric and adolescent patients?
A shortage of the chemotherapy drug leucovorin is causing some concern about patient care and the conduct of clinical trials
- Top Department Heads Step Down
- Gillanders Named an EGRP Branch Chief
- NCI Symposium Addresses Impact of Biospecimens on Cancer Research
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.
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Study Forecasts Savings for Marker-based Colorectal Cancer Treatment
Genetic testing to identify patients who will–and who won't–benefit from treatment is becoming the standard of care for some diseases.
Using the anti-EGFR therapy cetuximab 3 (Erbitux) to treat patients with metastatic colorectal cancer 22 who have the normal form of the KRAS gene—and not the mutant form—would save more than $600 million annually, according to study results presented January 14 at the Gastrointestinal Cancers Symposium 23 in San Francisco.
Some health services researchers warned that the findings from a single study should be interpreted with caution, arguing that they may not adequately account for various factors that could limit the extent of the savings.
Calling it a “macroeconomic statement,” Dr. Nicole Mittmann, executive director of the Health Outcomes and PharmacoEconomics Research Centre at Sunnybrook Health Sciences Centre in Toronto and co-chair of the Working Group on Economic Analysis at the National Cancer Institute of Canada Clinical Trials Group, said the study provides a good first “global estimate” of potential savings from more targeted use of cetuximab and other anti-EGFR inhibitors in patients with metastatic colorectal cancer.
The study relied on an economic model that included the estimated incidence of metastatic colorectal cancer for 2008, the average cost of a commercial test for KRAS status, and—relying on data from the CRYSTAL trial 24—the average number of cetuximab doses each patient receives and the number of patients expected to have KRAS mutations. After subtracting the cost of testing all patients from the projected savings of giving the drug only to patients with normal KRAS, the final savings came to an estimated $604 million.
That might be a conservative figure, stressed the study’s lead author, Dr. Veena Shankaran from the Robert H. Lurie Comprehensive Cancer Center, during a press briefing, because it does not include savings associated with recurrent disease or with managing the toxicities related to treatment in patients with mutated KRAS.
Following the results from retrospective analyses of several large clinical studies, which showed that cetuximab has a clinical benefit only in patients who have normal KRAS, testing metastatic colorectal cancer patients for KRAS status is slowly becoming the standard of care, Dr. Jennifer Obel of NorthShore University HealthSystem said during the briefing.
On the same day the study’s findings were presented, the American Society of Clinical Oncology released its first-ever “provisional clinical opinion 2,” which advises that all patients with metastatic colorectal cancer undergo KRAS gene mutation testing to determine whether they are eligible for anti-EGFR therapy with cetuximab or a similar agent, panitumumab 4 (Vectibix).
Last November, the National Comprehensive Cancer Network added a similar recommendation to its guidelines on the treatment of colon 25 and rectal 26 cancers. (Free registration is required to view the links.)
Given the expense of new cancer therapies, Dr. Mittmann said, “The challenge has become, can you afford them? Treating only patients with genetic characteristics associated with improved clinical benefits may improve the affordability of these targeted agents.”
Most insurers are now routinely paying for KRAS testing, Dr. Obel noted, even though the FDA has yet to act on requests from the companies that manufacture cetuximab and panitumumab, ImClone (which was recently acquired by Eli Lilly) and Amgen respectively, to revise the drug labels so that they reflect the data on KRAS status and clinical benefit.
The FDA’s Oncologic Drugs Advisory Committee heard presentations 27 on the companies’ labeling change applications last month, but the committee was not asked to make a labeling recommendation.
Also from the GI Cancers Symposium
Specific mutations in the EGF gene in people with gastroesophageal reflux disease (GERD) are associated with higher esophageal cancer 28 risk compared with GERD patients who don't have the mutations, researchers from the University of Toronto and Harvard University reported at the 2009 Gastrointestinal Cancers Symposium 29 in San Francisco. The mutation did not have the same effect in patients who did not suffer from GERD. GERD is a known risk factor for esophageal cancer, but, according to the researchers who led the case-control study, this is the first time specific genetic mutations have been identified that may predict which people with GERD are at elevated risk of developing the malignancy. Patients with the EGF mutations who suffered from GERD more frequently or for at least 15 years were at the highest cancer risk.
Results from a phase II study presented by German researchers at the same meeting suggested an important new treatment option for patients with malignant neuroendocrine tumors of the midgut (or lower part of the small intestine), a rare cancer with few effective treatments. In the multi-institutional study, patients treated with the drug octreotide LAR (Sandostatin LAR) had a median time to tumor progression of 14.3 months, compared with 6 months in patients who received a placebo. At 6 months, 64 percent of patients treated with the drug had stable disease, versus 37.2 percent of patients in the placebo arm. Overall survival data are not yet available. During a press briefing, Dr. Jennifer Obel from NorthShore University Health System in Illinois called the study results "practice changing."
Removal of Ovaries and Fallopian Tubes Cuts Cancer Risk for BRCA1/2 Carriers
Surgery that removes the ovaries and fallopian tubes, called salpingo-oophorectomy, is one of the most effective ways to decrease a woman's risk of breast and gynecologic cancer if she carries a BRCA1 or BRCA2 gene mutation. However, the true degree of risk reduction has not been precisely defined. A new meta-analysis 30 of 10 independent studies has revealed with greater confidence than ever before that the risk reduction of this surgery can be 80 percent for ovarian 31 or fallopian tube cancer and 50 percent for breast cancer 32. The full results of the analysis appeared online January 13 in the Journal of the National Cancer Institute.
A team of researchers led by Dr. Timothy R. Rebbeck of the University of Pennsylvania looked at overall breast cancer risk, breast cancer risk according to BRCA mutation, and ovarian or fallopian cancer risk. Women who had BRCA1 mutations and women who had BRCA2 mutations benefited equally in terms of breast cancer risk after the surgery, according to their analysis. The authors pointed out, however, that this conflicts with results from their previous prospective cohort study which indicated that the surgery may have more benefit for BRCA2 mutation carriers.
“[Studies] that used retrospective cohort or case-control approaches did not observe this difference, and therefore, there was no difference in the pooled estimates,” they wrote, noting that the issue deserves further investigation. Data were not available for the meta-analysis to make this BRCA-type distinction for gynecologic cancer risk after the surgery.
In a related editorial 33, Drs. Mark H. Greene and Phuong L. Mai of NCI's Division of Cancer Epidemiology and Genetics 34 commended the study authors, noting that their attempt to “disentangle potential differences between BRCA1 and BRCA2 mutation carriers who, despite having superficial similarities with regard to phenotype, have important biological differences” strengthens the findings of their report. “The risk estimates presented in the study represent the most accurate current measures of potential benefits from risk-reducing salpingo-oophorectomy,” said Dr. Greene, “and genetics providers should use them in their daily practice.”
Double Transplantation of One's Own Stem Cells Is Not Warranted for Multiple Myeloma
The addition of a second (tandem) hematopoietic stem cell transplant (HSCT) procedure using one's own (autologous) blood cells does not appear to improve either event-free or overall survival in multiple myeloma 35, according to a meta-analysis 36 of trials comparing single versus tandem transplants head-to-head published online January 13 in the Journal of the National Cancer Institute. Researchers led by Dr. Ambuj Kumar at the H. Lee Moffitt Cancer Center and Research Institute concluded that “the routine use of tandem transplant in its current form is not justified.”
This conclusion reflects another finding in their review: While the response rate improved 21 percent in patients receiving tandem treatments, the risk of treatment-related mortality (TRM) increased by 71 percent in this group. The data were drawn from six randomized controlled trials published or presented at meetings since 2003, in which a total of 1,803 patients were enrolled.
Multiple myeloma is a rarely curable malignancy of blood plasma cells that is nonetheless highly treatable, especially when certain patients are conditioned with different chemotherapy combinations before undergoing autologous HSCT. Tandem transplantation became feasible in the early 1990s, and these six trials were subsequently mounted to determine its value and safety in clinical practice.
While the earliest trial published in 2003 showed tandem transplantation improved overall and event-free survival, the authors of the meta-analysis noted that those results 37 “also indicated that tandem transplant may not benefit all patients equally,” and that the subsequent trials did not stratify patients according to biologic and genomic factors that are thought to influence risk. Therefore, they wrote, “it is not known if a benefit in terms of [overall survival] may exist” in a subgroup of patients receiving the tandem treatment, “or if a survival benefit might emerge as strategies to reduce TRM are improved.”
Race May Not Be a Survival Factor in Triple-negative Breast Cancer
Compared with white women, young African American women have a higher incidence 38 of triple receptor-negative (TN) breast cancer, tumors that don't respond to treatment with hormone therapy or trastuzumab 39 (Herceptin). This higher incidence has been proposed as the principal biological factor that, along with social and economic factors, may contribute to why African American women have higher breast cancer mortality rates compared with white women.
Now, a new study 40 from investigators at the University of Texas M.D. Anderson Cancer Center published in the January 10 Journal of Clinical Oncology suggests that African American and white women with TN breast cancer treated at the same institution under the same treatment conditions have similar survival outcomes.
The investigators reviewed data collected from 471 women with TN breast cancer who were treated with preoperative chemotherapy at M.D. Anderson between 1996 and 2005. All of the women underwent surgery after chemotherapy and received radiation therapy if their tumors had not responded to the preoperative chemotherapy. The proportion of women who received mastectomy versus breast-conserving surgery and who had lymph nodes removed did not differ significantly between racial groups.
Sixty-eight percent of African American women experienced a 3-year recurrence-free interval after treatment, compared with 62 percent of white women or women of other racial groups. Three-year overall survival was 71 percent for both groups. Women in both groups who had a pathologic complete response to preoperative chemotherapy (absence of invasive disease in the breast or axillary lymph nodes) had improved survival.
“We hypothesize that when similar treatment and follow up are delivered within a specialized cancer institution to women with TN disease, survival among black and white/other patients is similar. These observations need to be confirmed in a larger prospective study,” concluded the authors.
Method Could Reveal Fused Genes in Common Cancers
Researchers have developed a way to search for genes that are inappropriately fused in cancer cells and that may drive the disease. These gene rearrangements are common in cancers of the blood, and recent studies 41 have suggested that they may be important in other tumor types as well, particularly prostate and lung. But until now there has been no efficient way to hunt for them.
A team led by Dr. Arul Chinnaiyan of the University of Michigan Medical School and an NCI Early Detection Research Network 42 (EDRN) investigator developed a solution called “integrative transcriptome sequencing.” The method involves using two types of “next-generation” sequencing techniques to analyze messenger RNA from cancer cells. This generates relatively long RNA sequences that become scaffolds for assembling many shorter sequences (produced by another technology). The integration is critical because each method on its own yields many false-positive results, the researchers reported 43 online in Nature January 11.
As a demonstration of the technique, the team “re-discovered” known fusions, including BCR-ABL1 in chronic myelogenous leukemia 44, as well as previously unknown examples. Once a fused gene has been found, the researchers stress, the next steps include asking whether the fusion occurs in other patients and contributes to cancer progression.
“The whole field is looking for these fusions, and our study shows that you can find them using next-generation sequencing and by focusing on the RNA of cancer cells,” said Dr. Chinnaiyan. Fused genes represent an underappreciated class of mutations that may be missed by sequencing the genomes of tumor samples, he added.
Prelude to a New Chapter in the National Cancer Program
Dr. John E. Niederhuber
One week ago today the country inaugurated Barack Obama as our new president, an occasion accompanied by the excitement associated with such a historic election. This election and this transition in government will one day generate many books, in part because of the economic crisis that in many ways rivals that of the 1930s and the fighting of two wars. With the election of the first African American president, it’s impossible not to draw the connection between President Lincoln’s second inauguration and this inauguration and the tremendous progress our democracy has made possible. For many of us, there were certainly memories of the 1961 inauguration of the young and energetic President Kennedy, as well.
There are great expectations that the new president will make significant changes—changes that will touch nearly every aspect of our daily lives, patient care and cancer research included. As a citizen and as NCI director, I share those expectations, the anticipation, and excitement of hope. The hope for an adjustment to our country’s compass toward a renewed investment in science, in the creation of new knowledge, and in the education of our talented young people. This, I believe, is about our future—our future as world leaders.
The inauguration of President Barack Obama at the U.S. Capitol on Tuesday, January 20, 2009
NCI’s leadership has been eagerly anticipating this administration change and actively planning and providing input and new ideas about the unique features of the cancer research enterprise as a model of how to leverage changes in policy, research funding, and science infrastructure to maximize the impact of discovery on health care. And we are carefully considering how to narrow the formidable gap between the rapid pace of innovation in biomedicine and our ability to harness it to improve not only the health of individuals but the need to manage cost. Today and tomorrow, in fact, the NCI Executive Committee—along with some of our country’s top scientific minds—is holding a retreat to discuss the next frontiers of cancer research.
Clearly, President Obama has the future of biomedical research on his mind. In his inauguration speech, one line in particular stood out to me: “We will restore science to its rightful place,” he said, “and wield technology’s wonders to raise health care’s quality and lower its cost.”
The Administration's Cancer Agenda
That one line in an 18-minute speech encapsulates just what cancer research has accomplished and can continue to do, even more productively, if we pursue the most worthy science and use our resources wisely. By investing in discovery and creating knowledge, we can dramatically minimize the cancer burden and do it more cheaply than is possible today. Creating the ability to match the right patient with the right therapeutic solution means we will not be wasting treatment dollars.
Examples of this potential already exist. In particular is the wealth of data now showing that cetuximab 3 (Erbitux) only benefits colorectal cancer patients who have normal forms of the KRAS gene. As the Featured Article 6 in this week’s issue of the NCI Cancer Bulletin details, the annual cost savings to be reaped from the more tailored use of this targeted agent may be substantial. In a similar vein, the initial results 45 from The Cancer Genome Atlas 46 (TCGA) revealed valuable new information about one of the most intractable tumor types, glioblastoma multiforme 47 (GBM), by identifying what appears to be a mechanism of resistance to a chemotherapy drug commonly used to treat it.
Clinical practice is already changing based on the KRAS data, and the TCGA results have similar potential to help optimize available therapies, sparing patients unnecessary toxicities and, in the process, leading to more cost-effective treatment.
It’s important to stress, however, that optimally employing already existing knowledge and systems can lead to substantial gains against cancer. In a commentary 48 in the January 2009 The Oncologist, NCI Division of Cancer Treatment and Diagnosis 49 Director Dr. James Doroshow, NCI Division of Cancer Control and Population Sciences 50 Director Dr. Robert Croyle, and I recommend five areas where modest investments can build upon existing programs and partnerships to achieve important research ends and yield dramatic improvements in the prevention and treatment of cancer.
One such action involves expanded tobacco control efforts. In California, for example, 5 years after implementing its state-wide, comprehensive tobacco control program, not only did smoking rates drop dramatically, but there was an estimated $86 billion in health care cost savings. Instituting such comprehensive tobacco control programs more broadly would prevent many cancers, and the cost of that investment would easily be offset by the savings of a downturn in tobacco-related diseases.
NCI leadership recognizes that advances in informatics will also play a critical role in this regard and has launched the BIG Health initiative 51 to bring together, in a novel organizational framework, a continuum of information management aimed at empowering personalized medicine through the use of electronic medical records and a community of users including consumers, payers, and local physicians.
The realities on the ground have changed dramatically over the past 6 months. But, as others have said, crisis is often accompanied by great opportunity. With the incoming administration, NCI and the cancer community have an opportunity to demonstrate that we are amply prepared to wield science and technology to tackle one of the most difficult challenges facing our country’s people. In doing so, we can provide idea models and evidence-based programs for testing proposed changes in health care that will universally raise the quality of our nation’s well-being. The investment in the science and in care of patients with cancer remains the best model for understanding the genetics and biology of diseases in general, as well as the social and economic issues of delivering affordable health care to everyone.
Dr. John E. Niederhuber
Director, National Cancer Institute
A Conversation with Dr. Richard Troiano
Dr. Richard Troiano 52 is an epidemiologist in the Risk Factor Monitoring and Methods Branch 53 of NCI’s Division of Cancer Control and Population Sciences 50 (DCCPS). In 2006, he was detailed to the U.S. Department of Health and Human Services (HHS) Office of Disease Prevention and Health Promotion to help develop the first-ever federal Physical Activity Guidelines for Americans 54, which were released last fall.
Dr. Richard Troiano
What are the goals of the Guidelines?
The Physical Activity Guidelines are designed to provide information and guidance on the types and amounts of physical activity that provide substantial health benefits for Americans aged 6 years and older. The main idea behind the Guidelines is that regular physical activity can produce long-term health benefits.
Being physically active is one of the most important steps Americans can take to improve their health. The Guidelines note that some activity is better than none, and more activity is even better. Both aerobic and muscle-strengthening activities are beneficial. Many health benefits occur with at least 2 hours and 30 minutes of moderate-intensity physical activity per week or the equivalent 1 hour and 15 minutes of vigorous-intensity activity. Aerobic activity should be performed in episodes of at least 10 minutes, and preferably spread throughout the week. To gain additional and more extensive health benefits, adults can increase their aerobic physical activity to 5 hours a week of moderate-intensity or 2 hours and 30 minutes a week of vigorous-intensity aerobic physical activity or an equivalent combination of moderate- and vigorous-intensity activity. Adults should do muscle-strengthening activities on at least 2 days a week.
What are their implications for cancer control?
The HHS Physical Activity Guidelines Advisory Committee examined both cancer prevention and benefits for cancer survivors as outcomes related to physical activity. Physical activity was clearly shown to reduce the risk of cancers of the colon 22 and breast 32, and it may also reduce the risk of cancers of the endometrium 55 and lung 56.
It appears that a relatively large amount of physical activity is required to see a reduction in cancer risk—about 3.5 to 7 hours per week. This is toward the upper end of the recommended range for health benefits in the Guidelines. However, cancer survivors seem to have noticeably improved fitness and quality of life even with amounts of physical activity at the low end of the recommended range. Just getting a 30-minute walk three times a week may provide benefits.
What is NCI’s research agenda for examining the link between physical activity and reduced cancer risk?
NCI supports a broad variety of research related to physical activity and cancer. One example is the Health, Eating, Activity, and Lifestyle (HEAL) Study 57 that examines relationships among physical activity, biomarkers, and breast cancer prognostic factors, as well as intermediate outcomes and recurrence in women with early stage breast cancer.
NCI is also stimulating novel research in the assessment of physical activity. Through the Improving Diet and Physical Activity Assessment 58 Program Announcements and the Exposure Biology Program 59 of the Genes, Environment and Health Initiative, grants have been awarded to develop and validate new objective measures of physical activity that use motion sensors, heart rate monitors, and geographic location sensors. These devices will enhance our understanding of the relationship between physical activity and health.
Lowly Fruit Fly Reveals Genetic Factors in Cancer and Metastasis
For more than a century, Drosophila melanogaster, a species of common fruit fly, has been an indispensable model organism for genetics research. These flies thrive in the laboratory with minimal care and expense, reproduce rapidly, and possess an easily manipulated genome. The entire Drosophila genetic code has been sequenced, and Drosophila and humans share many genes that are known to cause disease.
Flies with a mutation in the RET oncogene, which leads to medullary thyroid cancer in humans, develop rough, non-functional eyes (middle). Treatment with the drug ZD6474, which targets RET, restored the eye cells to normal (right). A normal eye from a fly without the RET mutation is shown on the left for comparison. (Image courtesy of Dr. Marcos Vidal and Dr. Ross Cagan)
However, the use of Drosophila in cancer genetics has been fairly limited until recently. “Historically, people thought that Drosophila never grow tumors,” explained Dr. Tian Xu, professor of genetics at Yale University and an investigator with the Howard Hughes Medical Institute, whose laboratory has been testing uses for Drosophila in cancer research since 1993.
Early experiments where germline mutations (mutations in eggs or sperm) in genes suspected of playing a role in cancer development were introduced into fly lines failed: These flies carried the mutations in every cell in their body, and their offspring were not viable—they died in the embryonic stage.
Mimicking Human Tumor Formation
To create a model system that more closely mimicked human tumor formation, Dr. Xu's laboratory developed a genetic mosaic model that allowed them to mutate genes in individual somatic cells at different stages of a fly's development. These flies successfully matured and developed tumors in the target organs.
Dr. Xu and his colleagues have since used their mosaic model to identify and study many tumor suppressor genes in Drosophila that were later recognized as having orthologs (genes derived from a common evolutionary ancestor) or conserved properties in humans, such as PTEN's role in regulating cell growth. They also used Drosophila to elucidate the cell signaling pathway involved in tuberous sclerosis complex (TSC), a genetic disorder in which tumors form in many organs. They found that blocking downstream components of the pathway can suppress TSC-associated tumor formation. Now, the drug rapamycin, an inhibitor of the pathway, is being tested in clinical trials for TSC and brain tumors.
“When we first proposed studying tumor suppressors in flies, I didn't really imagine that our research could directly contribute to treatment in patients, so this was a really satisfying experience,” said Dr. Xu.
In recent years, his laboratory has focused on developing a Drosophila model of metastasis 60, which can be used to interrogate the contribution of individual genes to a cell's metastatic potential.
A Model of Tumor and Environment
Metastasis is also of great interest to Dr. Ross Cagan, professor of developmental and regenerative biology at the Mount Sinai School of Medicine. Originally trained in using Drosophila to test the cell signaling pathways that drive eye development, Dr. Cagan has developed several model systems that use Drosophila to directly screen potential anti-cancer and anti-metastasis drugs.
“Drosophila is the simplest model system that has classic epithelial tissues, with tumors that would actually react to drugs in the way they would in humans,” said Dr. Cagan. In addition, he explained, the sophisticated genetic tools available to Drosophila investigators allow them to insert four or more genes together into a fly chromosome. “We're looking at human sequencing data and asking what genes work together to form tumors. Then we can actually build those constructs in the fly,” he explained.
An early success for the Cagan laboratory came from their Drosophila model of MEN2 syndrome, an inherited condition that can result in the development of endocrine cancers, particularly medullary thyroid cancer 61 (MTC). Dr. Cagan's laboratory created flies that expressed the aberrant protein responsible for MEN2-associated MTC in their eyes, which developed rough and non-functional cells. The investigators then fed the flies drugs that could potentially suppress the aberrant protein, until they found one that restored the eyes to normal. That compound, called ZD6474 (Zactima), is now being tested in a phase II clinical trial 62 for MTC.
Dr. Cagan's laboratory has also developed a Drosophila model to test drugs targeting metastatic cancer cells. In their new model, the investigators have created a multi-gene system that causes cells in the fly wing to shed into the circulatory system as the fly develops (in the same way that metastatic cells leave a tumor), leaving the wing crumpled. The investigators then feed the flies potential anti-metastasis drugs and observe which compounds uncrumple the fly wing—in effect, reversing metastasis.
Since cancer progression and metastasis involve extensive interactions between cells and their environment, he explained, using flies instead of cell lines to screen drugs allows you to look at how a drug might affect these interactions in whole tissues. “If you want to look for effective anti-metastatic drugs,” he concluded, “you have to do it in a complete tumor, in a living system.”
Cancer Imaging Looks Beyond Jellyfish Genes
Jellyfish are drifters who mostly go where the currents take them. But the animals deserve some credit for sparking a revolution in how scientists track the movements and interactions of proteins in many kinds of cells, including cancer cells.
A green fluorescent protein was isolated from the jellyfish Aequorea victoria, above, in 1962. Copyright Sierra Blakely
Recognition came last year in the form of a Nobel Prize. Three scientists were honored for discovering the green fluorescent protein (GFP) in the jellyfish Aequorea victoria and turning it into a powerful research tool. In mice and other animals, the glow of GFP has illuminated aspects of biology that were long hidden from view, including the spread of cancer, the Nobel committee noted.
The magic of GFP is that the protein can glow outside of jellyfish. In a common experiment, GFP is genetically linked to another protein so that the activation of the linked protein turns on GFP as well, producing a telltale glow under the right light.
Since the first GFP was discovered in 1962, additional types and colors have been found in nature or developed in the lab. Recent studies have expanded the limits of what can be observed, and they have shown how this technology might be translated into a powerful imaging tool in the clinic.
Watching Cancer Spread
Scientists have used GFP to observe the spread of cancer cells in mice for up to several days, but a new method extends this observation period to weeks. The technique involves shining a special light on tumor cells that were engineered to produce a GFP-like protein derived from coral. When hit by the light, the cells turn from green to red, making it possible to track their movement.
A mammary tumor in a living mouse as seen through a mammary imaging window. Tumor cells are green and optically-marked tumor cells are red. The extracellular matrix is blue. (Image courtesy of Dr. Jacco van Rheenen)
As a demonstration, researchers in the Gruss Lipper Biophotonics Center (GLBC) at Albert Einstein College of Medicine tracked two populations of cells from the same breast tumor over several weeks. Mice in the study had “imaging windows” inserted into their mammary glands so that the researchers could easily find the cells at each inspection.
“Now that we can optically mark tumor cells by turning them from green to red, we can start to map the fates of these cells in the body,” said Dr. John Condeelis of GLBC, who co-led the study with his colleague Dr. Jeff Segall. Their findings 63 appeared in the December 2008 Nature Methods.
The study showed that tumor cells near blood vessels were more likely to spread to the lungs than other tumor cells, suggesting the importance of the local environment in the spread of cancer. “Even within the same tumor there were regions where you get different types of metastases,” said senior author Dr. Jacco van Rheenen, who is currently at the Hubrecht Institute in the Netherlands.
While the GFP toolbox has grown, the technology has the limitation that a protein must be encoded in the genome before it is produced. For use in patients with cancer, fluorescent compounds would likely have to be injected or given orally. A new study by researchers at NCI and in Japan suggests how this might work.
An activatable probe (right) shows a metastatic ovarian tumor with minimal background signals. The control "always on" probe (left) lacks clear delineation of cancer foci due to high background signals. (Image courtesy of Dr. Hisataka Kobayashi)
The team developed a fluorescent compound that can be attached to a tumor-specific antibody and only lights up when the antibody is taken inside living cancer cells. When the compound was tested in mice using the breast cancer drug trastuzumab 39 (Herceptin), the “probe” almost always hit its target.
“All we see are the healthy cancer cells,” said Dr. Hisataka Kobayashi of the Molecular Imaging Program 64 at NCI's Center for Cancer Research 65 (CCR). He developed a pH-sensitive antibody with Dr. Yasuteru Urano, a chemist at the University of Tokyo. Their study 66 appears this month in Nature Medicine.
Most imaging probes produce a signal even after a cell is damaged or dies, and they also bind to normal cells. This could be misleading to physicians who want to identify viable cancer cells. The new probe was designed to be activated exclusively in cells that pull it into a part of the cell called the lysosome. Because the lysosome maintains an acidic environment in healthy cells, a pH-sensitive probe such as this is largely active only in living cancer cells.
Into the Clinic
If developed further, the technology could possibly be used to diagnose cancer and monitor the effects of therapy almost in real time, said Dr. Kobayashi. Another potential application would be to guide surgeons as they try to remove tumor tissue from patients with cancers, he added.
As a step toward the clinic, NCI is collaborating on a clinical trial to test different imaging tools, including activatable probes, as a way to improve the treatment and detection of ovarian 31 cancer.
“With this disease, we know that better surgeries to remove the cancer lead to better outcomes,” said coauthor Dr. Peter Choyke, who directs the Molecular Imaging Program in CCR. “These activatable probes may improve the ability to detect the earliest signs of the disease and to improve outcomes.”
—Edward R. Winstead
Inhibiting Tumor Angiogenesis in Children
Name of the Trial
Phase I Study of Cediranib in Pediatric Patients with Refractory or Recurrent Extracranial Malignant Solid Tumors or Acute Myeloid Leukemia (NCI-06-C-0152). See the protocol summary 67.
Dr. Elizabeth Fox, NCI Center for Cancer Research
Why This Trial Is Important
Great progress has been made in the treatment of childhood cancers over the past 30 years, thanks primarily to advances in chemotherapy and a high level of participation in clinical trials by pediatric patients. This progress, however, is in danger of stalling without new treatment advances.
One approach that has shown effectiveness in the treatment of some adult cancers is inhibiting the growth of new blood vessels to tumors (i.e., blocking tumor angiogenesis). Without angiogenesis, solid tumors are unable to grow beyond a few millimeters in size. Because drugs that inhibit angiogenesis may cause different side effects 68 in children than they do in adults, it is important to carefully test their use in pediatric cancer patients.
In this trial, researchers are testing an angiogenesis inhibitor called cediranib 69 in pediatric patients who have solid tumors 70 (except brain tumors) or acute myeloid leukemia 71 (AML), a type of blood cancer. Although solid tumors are not formed in AML, there is evidence that a protein known to be important in tumor angiogenesis (i.e., vascular endothelial growth factor 72, or VEGF) may also be important for the growth of AML cells. Cediranib blocks all three known receptor proteins for VEGF.
“Solid tumors in children tend to be highly vascular, and adult AML patients with elevated levels of VEGF typically don't survive as long as those with lower levels,” said Dr. Fox. “So, there's a strong rationale for using VEGF inhibitors for these cancers. However, it is vitally important to assess the toxicities and establish the appropriate dosage of cediranib for pediatric patients.”
“Furthermore, we plan to study how cediranib affects a number of markers related to cancer progression and, at least preliminarily, determine tumor responses to cediranib in these patients,” she added.
For More Information
See the list of entry criteria 73 and trial contact information 74 or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.
Clinicians, Cooperative Groups Work through Leucovorin Shortage
A shortage of the chemotherapy drug leucovorin 75
is raising some concern about patient care and the conduct of clinical trials, researchers and patient advocates have reported in recent weeks.
Although it is used to treat several cancers, leucovorin in combination with another chemotherapy drug, fluorouracil 76 (often called 5-FU), is particularly important as part of the first-line therapy in patients with metastatic colorectal cancer 22 and adjuvant therapy for earlier stage disease, explained Dr. Meg Mooney, head of Gastrointestinal and Neuroendocrine Cancer Therapeutics in NCI's Division of Cancer Treatment and Diagnosis 49.
Leucovorin calcium (Image courtesy of Bedford Laboratories)
It's unclear whether the shortage has had a demonstrable impact on patient care across the country. According to Kate Murphy from the Colorectal Cancer Coalition, the organization has not received many calls from patients reporting problems with their care because of lack of access to the drug.
“We've been hearing it more from the people in the clinical trials who are concerned about amending protocols,” Ms. Murphy said. Even so, she added, that is no guarantee that more wide-spread issues won't arise.
Managing the Shortage
NCI's Cancer Therapy Evaluation Program 77 (CTEP) has provided general instructions to Cooperative Groups conducting CTEP-supported clinical trials on how to address the leucovorin shortage with regard to their specific protocols.
At Fox Chase Cancer Center in Philadelphia, the shortage initially “caused a fair amount of scrambling,” said Dr. Steven J. Cohen, a lead investigator on colorectal cancer trials at the center. The Eastern Cooperative Oncology Group, which runs a large number of colorectal cancer trials, quickly got word to facilities about the shortage, Dr. Cohen noted, so the staff worked with the pharmacy to secure enough levoleucovorin (Fusilev), an alternative form of leucovorin, to meet patient demand. Although levoleucovorin is not approved by the FDA for the treatment of colorectal cancer, it is often used off-label to treat it, according to a clinical alert issued by the American Society of Clinical Oncology.
“We wanted to make sure that for patients coming in to receive standard therapy, we had something for them,” he said. Sometimes that means alternating between standard leucovorin and levoleucovorin. Although dosing differences are an issue with levoleucovorin, the larger concern may be its vastly higher price tag, which is approximately 60 times higher than the generic leucovorin, Dr. Cohen said.
The experience differs from facility to facility, though. At Swedish Cancer Institute in Seattle, the leucovorin supply has been stable to date and has not had an impact on patient care or clinical trials, said Dr. Philip Gold, program leader of gastrointestinal cancers at that institute.
What's Behind It?
The shortage appears to have been brought on by manufacturing interruptions. Two companies produce leucovorin, Bedford Laboratories and Teva Pharmaceuticals. According to the most recent statement from Bedford, released nearly 5 weeks ago, supply interruptions of its leucovorin product are due to ongoing efforts at its Ohio manufacturing facility to expand production capacity.
“We anticipate resolution of these issues in the near future. Until such time, we will work diligently to fulfill our order commitments,” the December 18 statement said.
Teva has had no manufacturing issues that would slow production of its leucovorin product, according to a company spokesperson. However, in response to the shortage it has ramped up production and is releasing product as frequently as it can, the spokesperson said.
Top Department Heads Step Down
Dr. Richard Besser
Dr. Frank Torti
In addition to Secretary Michael Leavitt stepping down as head of the Department of Health and Human Services 78, several other notable changes in top agency positions occurred on January 20.
Dr. Andrew C. von Eschenbach officially resigned as FDA commissioner. Dr. von Eschenbach served as NCI director from January 2002 until he was appointed to lead the FDA in September 2005. In a farewell message to employees, he stated, "The 3 years I have been at the agency have been a pivotal period—for in that time we have seen the increasingly rapid and radical changes resulting from both globalization of the marketplace and advancements in science and technology that are ushering in the molecular era of health care."
Dr. Frank Torti 79, the FDA's principal deputy commissioner and chief scientist, will serve as acting FDA commissioner until a replacement is appointed.
Also stepping down last Tuesday was the director of the CDC 80, Dr. Julie Gerberding. She was replaced in an acting capacity by Dr. Richard Besser 81.
Gillanders Named an EGRP Branch Chief
Dr. Elizabeth Gillanders
Dr. Elizabeth Gillanders was recently appointed chief of the Host Susceptibility Factors Branch (HSFB) in the Epidemiology and Genetics Research Program 82 in NCI's Division of Cancer Control and Population Sciences 50. Dr. Gillanders received her Ph.D. in genetic epidemiology from Johns Hopkins University.
Before joining NCI, she worked at the National Human Genome Research Institute (NHGRI), where she headed its intramural Genetic Epidemiology Unit within the Cancer Genetics Branch. Her applied research at NHGRI focused on genetic epidemiology of cancer susceptibility, with an emphasis on melanoma, prostate cancer, and breast cancer epidemiology. She also investigated new ways to improve the power of conventional methods for gene discovery for complex traits.
As branch chief of HSFB, she oversees epidemiologic research in the etiology of cancer in human populations related to personal susceptibility factors such as genetic, epigenetic, immunological, and hormonal biological pathways.
NCI Symposium Addresses Impact of Biospecimens on Cancer Research
NCI will sponsor the second annual Biospecimen Research Network Symposium, “Advancing Cancer Research through Biospecimen Science,” March 16–18 in Bethesda, MD. The symposium will address the impact of pre-analytical biospecimen variables on cancer research and molecular medicine.
Hosted by NCI's Office of Biorepositories and Biospecimen Research 84, this symposium brings together the broad range of stakeholders whose work involves biospecimens, including research investigators, clinicians, pathologists, industry representatives, hospital administrators, and patient advocates. To register online, go to http://brnsymposium.com.