The addition of chemotherapy to radiation therapy doubled the median survival time for certain patients with an aggressive form of oligodendroglioma, a rare brain tumor. Patients in the study had anaplastic oligodendrogliomas, but only those whose tumors contained a genetic abnormality known as the 1p19q co-deletion experienced a benefit from adding chemotherapy to radiation.
The finding, from a phase III trial in which patients were followed for a median of 11 years, will lead to changes in an ongoing NCI-sponsored clinical trial as well as in the standard of care for patients who are not enrolled in a clinical trial. NCI and the Radiation Therapy Oncology Group (RTOG) announced the finding January19 in coordinated press releases. Read more > >
Drs. Katherine McGlynn and Mary Ward discuss recent activities and future plans of the NCI Women Scientist Advisors, a group created to represent the career interests of women scientists at NCI and NIH.
Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.
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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Genetic Abnormality Predicts Treatment Benefit for Patients with Rare Brain Tumor
The addition of chemotherapy to radiation therapy doubled the median survival time for certain patients with an aggressive form of oligodendroglioma, a rare brain tumor. Patients in the study had anaplastic oligodendrogliomas, but only those whose tumors contained a genetic abnormality known as the 1p19q co-deletion experienced a benefit from adding chemotherapy to radiation.
The finding, from a phase III trial in which patients were followed for a median of 11 years, will lead to changes in an ongoing NCI-sponsored clinical trial as well as in the standard of care for patients who are not enrolled in a clinical trial. NCI and the Radiation Therapy Oncology Group (RTOG) announced the finding January 19 in coordinated press releases (here and here).
Among patients whose tumors carried the abnormality, those treated with chemotherapy and radiation survived a median of 14.7 years, compared with a median of 7.3 years for those who received radiation alone.
The investigators took the unusual step of announcing the findings publicly before presenting them at a scientific meeting because of their importance for the treatment of other brain tumor patients.
"We wanted to share this information to ensure that patients have access to the most effective therapy," said Dr. Walter Curran of Emory University, a senior author of the study and RTOG group chairman. RTOG conducted the trial, known as RTOG 9402, in collaboration with four other NCI-sponsored cooperative groups.
In the trial, which began in 1994, 291 patients with oligodendrogliomas were randomly assigned to receive either standard therapy with radiation alone or radiation plus a multidrug chemotherapy regimen consisting of the drugs procarbazine, lomustine, and vincristine (PCV).
Results at a minimum follow-up time of 3 years, published in 2006, showed no overall survival benefit for the patients who received chemotherapy. Regardless of treatment assignment, however, patients whose tumors carried the 1p19q co-deletion survived significantly longer than those whose tumors did not have the co-deletion (more than 7 years versus 2.8 years).
The new analysis, based on much longer follow-up of over 11 years, provides "strong evidence that the chromosomal structure of 1p and 19q co-deletion can be used as a marker to determine which patients will benefit from combined chemotherapy and radiation therapy," said principal investigator Dr. Gregory Cairncross of the University of Calgary in Canada.
Oligodendrogliomas, tumors that form in the brain's nerve tissue, make up about 9 percent of all primary tumors of the brain and central nervous system. They occur primarily in adults; the average age at diagnosis is 35. Roughly half of patients have tumors that contain the 1p19q co-deletion, in which parts of chromosomes 1 and 19 are simultaneously deleted.
The new findings mean that "initial management with radiation and chemotherapy should be considered the standard of care for patients with the co-deletion because of the survival benefit," said Dr. Curran.
For patients whose tumors contained only one chromosomal deletion (either 1p or 19q) or no deletion, survival was similar whether they received radiation alone or radiation plus chemotherapy (2.6 years versus 2.7 years).
The announcement of the findings resulted in immediate suspension of enrollment in an ongoing NCI-sponsored clinical trial in which patients with an aggressive brain tumor, anaplastic glioma, with the 1p19q co-deletion were being randomly assigned to treatment with radiation alone or radiation plus chemotherapy with the drug temozolomide. This international trial, dubbed CODEL, had been enrolling patients across North America and in Europe.
"Because our trial showed that treatment with radiation alone is inferior to chemotherapy plus radiation in patients with the co-deletion, it became necessary to immediately suspend accrual to CODEL and consider how the trial should be altered and how patients randomized to radiation therapy alone should be managed," Dr. Cairncross wrote in an e-mail.
"We cannot continue randomly assigning patients whose tumors have the 1p19q co-deletion to the radiation-only treatment arm now that we know chemotherapy plus radiation is superior," said Dr. Malcolm Smith of NCI's Cancer Therapy Evaluation Program, which oversees trials conducted by NCI-supported cooperative groups. "Patients not enrolled in clinical trials should also benefit from this new information."
Dr. Cairncross and his co-authors have submitted an abstract of the trial results for presentation at the American Society of Clinical Oncology annual scientific meeting in Chicago in June.
Cancer Research Highlights
Ovarian Cancer Patients with BRCA Mutations May Fare Better than Non-Carriers
A large, multicenter study shows that women with ovarian cancer who have mutations in the BRCA1 or BRCA2 genes have better survival rates than women who do not have such mutations. The study is also the first to provide strong evidence that ovarian cancer prognosis is better for women with BRCA2 mutations than women with BRCA1 mutations. The results were published online today in JAMA.
Inherited mutations in BRCA1 and BRCA2 are the strongest known genetic risk factors for breast cancer and epithelial ovarian cancer, the most common form of ovarian cancer. These mutations are found in 6 to 15 percent of women with epithelial ovarian cancer; the relative prognosis for women who carry BRCA gene mutations compared with non-carriers has remained unclear due to differing study results.
“Because BRCA mutations are rare to begin with, and because ovarian cancer is also relatively uncommon, it’s hard to design studies that are big enough to provide definitive evidence on this question,” explained lead author Dr. Kelly Bolton, a UCLA medical student who is affiliated with the Laboratory of Translational Genomics in NCI’s Division of Cancer Epidemiology and Genetics.
Dr. Bolton and her colleagues combined data from 26 clinical research studies worldwide on the survival of women with ovarian cancer. This included data on 1,213 women with inherited BRCA1 or BRCA2 mutations and 2,666 women without these mutations. The women were followed for variable times between 1987 and 2010.
The research team’s analysis showed that the 5-year overall survival rate for ovarian cancer was 36 percent for non-carriers, 44 percent for BRCA1 mutation carriers, and 52 percent for BRCA2 mutation carriers. After adjusting for the stage and grade of a patient’s tumor at the time of diagnosis, as well as other factors that could affect prognosis, the researchers found that BRCA2 mutation carriers are twice as likely to survive than non-carriers in the 5 years following diagnosis, whereas BRCA1 mutation carriers have a 37 percent greater chance of survival in the 5 years following diagnosis than non-carriers.
“Our findings provide further support that BRCA1 and BRCA2 mutation carriers’ tumors are different biologically, and they should be treated separately,” said Dr. Bolton. “That’s really important for clinical trial design, especially if you’re studying drugs such as PARP inhibitors, which are being tested in BRCA1 and BRCA2 mutation carriers.”
The findings could eventually be used by clinicians when advising patients with ovarian cancer about their possible prognosis but further studies are needed, Dr. Bolton added.
Experimental Drug Improves Survival in Previously Treated Metastatic Colorectal Cancer
Treatment with the investigational agent regorafenib modestly improved survival for patients with metastatic colorectal cancer whose disease had progressed after multiple prior treatments, according to clinical trial results presented last week at the 2012 Gastrointestinal Cancers Symposium.
The trial’s Data and Safety Monitoring Committee stopped the trial after a preplanned interim analysis showed a 1.4-month improvement in median overall survival, said the trial’s lead investigator, Dr. Axel Grothey of the Mayo Clinic Cancer Center in Minneapolis.
In the trial, called CORRECT, 760 patients were randomly assigned to receive regorafenib in combination with best supportive care—that is, care designed to treat symptoms but not to cure the underlying disease—or a placebo and best supportive care. Regorafenib, which comes in pill form, targets several specific enzymes known as kinases that regulate key tumor cell processes, including cell growth and proliferation.
The median overall survival was 6.4 months for patients who received regorafenib and 5 months for patients who received the placebo. After the randomized phase of the trial was stopped, patients in the placebo arm could choose to cross over and receive regorafenib.
Approximately two-thirds of the patients in the trial had received at least four prior treatments. Common side effects of regorafenib included skin rash, fatigue, diarrhea, and hypertension, which could be managed with medications and dose reductions, Dr. Grothey explained.
Fewer than 2 percent of the patients who received regorafenib experienced significant tumor shrinkage. But 44 percent of patients who received regorafenib had no measurable tumor growth or worsening of symptoms compared with 15 percent of patients treated with placebo.
Unlike many chemotherapy drugs and targeted agents, which are cytotoxic—that is, they kill cancer cells—regorafenib appears to be primarily cytostatic, meaning it arrests tumor growth, Dr. Grothey noted.
Other primarily cytostatic agents are in development. Traditional measures of treatment efficacy, such as tumor shrinkage, will have to be reconsidered, Dr. Grothey noted, or “we might miss agents that are cytostatic” and can help control tumor growth and progression.
Last year the Food and Drug Administration granted regorafenib, which is manufactured by Bayer, “fast track” designation for the treatment of patients with metastatic colorectal cancer whose disease has progressed despite multiple treatments with FDA-approved drugs. The fast-track process is designed to expedite the agency’s review of treatments for diseases with unmet needs.
Differences in Estrogen Metabolism May Influence Breast Cancer Risk
The way a woman’s body processes, or metabolizes, the hormone estrogen may influence her risk of postmenopausal breast cancer, according to new data from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) published online January 9 in the Journal of the National Cancer Institute.
In postmenopausal women, higher levels of estrogen are known to be associated with an increased risk of breast cancer. Laboratory work, however, has suggested that how estrogen is metabolized may also be important for risk. Two major hypotheses for the role of estrogen metabolites have dominated the field: one, that specific metabolites stimulate tumor growth and progression; and two, that specific metabolites function as mutagens and initiate DNA damage that can turn a normal cell into a cancerous one. This study confirms that estrogen metabolism is important and lends credence to both hypotheses.
“Those are the results we’re most excited about and also the most cautious about, because it’s the first time that we’ve been able to measure the relevant metabolites in blood in an epidemiologic setting,” said Dr. Barbara Fuhrman, a postdoctoral fellow with DCEG and lead author of the study. She and her colleagues used a novel liquid chromatography/mass spectrometry assay that allowed them to measure 15 different parent estrogens and estrogen metabolites accurately at the very low concentrations present in postmenopausal women.
They performed their analyses on blood samples taken from women enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Researchers compared the blood samples of 277 postmenopausal women who later developed breast cancer and 423 matched women without the disease. None of the women were taking menopausal hormone therapy at the time of blood collection.
Apart from the expected strong relationship with estradiol, the researchers found no clear relationships between individual hormone and metabolite concentrations and cancer risk. When they considered relationships among the three major estrogen metabolic pathways and their components, the clearest patterns emerged when they compared the pathways to one another and to the total pool of parent estrogens available for metabolism. Two metabolic patterns seemed to influence breast cancer risk in a statistically significant manner independent of circulating estradiol. One pattern was associated with an increased risk of breast cancer, whereas the other was associated with a decreased risk. When the researchers included a measure of each of these patterns in an established risk prediction model for breast cancer, the calculated risk for a considerable number of the women changed substantially.
“Although these findings are of great research interest, they need to be replicated and there are no immediate clinical implications,” said Dr. Regina Ziegler, also of DCEG and the senior author on the study. “We are still at the beginning of our understanding of the complex role of estrogen in the etiology of breast cancer. By improving our knowledge of the role of estrogen metabolism, we may uncover novel strategies for chemoprevention and treatment and be better able to predict an individual’s risk of breast cancer.”
Epigenetic Study Suggests Possible Treatment for Retinoblastoma
Based on a new model of the genetic and epigenetic changes underlying the childhood cancer retinoblastoma, researchers have identified a potential strategy for treating this rare disease. The model, published online in Nature January 11, suggests that inhibiting a protein called spleen tyrosine kinase (SYK) could benefit patients with this cancer of the eye.
Drugs that inhibit SYK are being developed to treat blood cancers and certain other diseases. In cell cultures and animal models, two of these drugs killed retinoblastoma cells, researchers with the Pediatric Cancer Genome Project found.
Both copies of a gene called RB1 are inactivated in nearly all retinoblastomas, but other molecular changes are required for the disease to progress rapidly. To identify additional DNA alterations, the researchers sequenced the tumor and normal genomes of four affected patients.
The analysis did not reveal any suspicious mutations or structural changes in the genome, however. “This was really surprising,” said Dr. Michael Dyer of St. Jude Children’s Research Hospital and the study’s senior author. “We wondered how these tumors could progress as rapidly as they do.”
In a further analysis based in part on a previous study, the authors focused on epigenetic changes, including DNA methylation and histone modification, which can alter the activity of genes without causing changes in the DNA sequence. When they compared the epigenetic profiles of normal cells and cancer cells, new clues about the disease emerged.
Several cancer-related genes in retinoblastoma cells appeared to be regulated by epigenetic mechanisms, including the SYK gene.
Although SYK has no known function in the eye, the protein may increase the production of a protein called MCL1 that is important for the survival of retinoblastoma cells. Blocking SYK may reduce the amount of MCL1 and trigger the death of retinoblastoma cells, the study authors said.
As a next step, the researchers have begun to develop a formulation of the most relevant SYK inhibitor, called R406, for the eye. The new formulation might provide a way to get more of the drug into the eye, Dr. Dyer said. But the researchers need to assess the potential toxicities of this version of the drug before planning a clinical trial, he added.
A Conversation With
A Conversation with the NCI Women Scientist Advisors
The NCI Women Scientist Advisors Committee hosted a career development luncheon January 12 at the annual NCI Intramural Scientific Investigators Retreat. The NCI Women Scientist Advisors are composed of representatives from NCI's two internal (intramural) research groups, the Center for Cancer Research (CCR) and Division of Cancer Epidemiology and Genetics (DCEG). Representatives from DCEG, Drs. Katherine McGlynn and Mary Ward, talked with the NCI Cancer Bulletin about the Women Scientist Advisors' role at NCI. CCR's representatives are Drs. Ying Zhang, Brigitte Widemann, and Cheryl Ann Winkler.
Who are the NCI Women Scientist Advisors and what sort of programs and activities are you involved with?
NCI Women Scientist Advisors are part of the NIH Women Scientist Advisors Committee, which was established in 1993 when Dr. Bernadine Healy was NIH director. Dr. Healy created a task force to address concerns about the small proportion of women scientists who were senior investigators at NIH and about pay equity and work-life balance issues. The task force recommended that each NIH institute and center have a Woman Scientist Advisor who was a senior woman scientist.
Our responsibilities at this year's NCI Intramural Retreat included organizing a career development luncheon, sponsoring the NCI Rosalind E. Franklin Award Lecture for Women in Cancer Research, and awarding the annual Women Scientist Advisors mentoring and leadership awards for NCI senior investigators. Dr. Titia de Lange, a professor and scientist at Rockefeller University, received the Rosalind E. Franklin award this year and gave a tremendous talk about her research on the role of telomeres in protecting chromosomes. The NCI Women Scientist Advisors mentoring award recipients were Dr. Shelia Zahm of DCEG and Dr. Lee Helman of CCR.
In addition to the NCI Principal Investigator Retreat activities, the Women Scientist Advisors support and promote career development for the NCI scientific community and address issues that women scientists may face.
What was the theme of this year's luncheon?
This year's theme was "Focusing Your Science and Promoting Your Career: Steps to Make Your Career More Productive." Nearly 200 NCI researchers, male and female, attended. The lunch is open to all NCI scientists, and this year's theme was relevant to men and women scientists. The first topic was about promoting your science and networking in the face of budgetary and resource constraints. The other two topics were about assertive and effective communications and time management. We had eight roundtables for each of the topics, which allowed for discussion.
NCI Director Dr. Harold Varmus and the Rosalind E. Franklin award winner Dr. Titia de Lange were asked to add their thoughts on each of the three luncheon topics. Dr. Varmus noted the importance of considering work-life balance for all scientists and the importance of creating a more ethnically diverse workplace at NCI. Dr. de Lange encouraged women to speak their minds and to not concern themselves about being perceived as nice. She also promoted the idea of the three Ds: Do it now, Delegate, and Don't worry.
What other activities will NCI Women Scientist Advisors pursue in the coming year?
Since one of our main goals is to promote the careers of female scientists at NCI and NIH, whenever we have outside guests or visiting scholars, we try to find an opportunity for NCI scientists to meet with those visiting researchers. For example, we sponsor brown bag lunches with these guests that are open to anyone who wants to attend. If the guest is a female scientist, we organize an informal lunchtime discussion where she can provide pointers on how she got to her current position.
This past fall, for example, Dr. Silvia Franceschi, of the International Agency for Research on Cancer, visited NCI and participated in a brown bag lunch. Rather than deliver prepared remarks, Dr. Franceschi invited attendees to ask her questions, which she answered very candidly and openly. People asked questions such as: "How do you know when it's time in your career to move to another institution?" and "How frequently should you move to other institutions?" and "How do you get along in institutions that are male-dominated?" Dr. Franceschi was very insightful, and we literally ran out of time. It was quite lively!
—Interviewed by Bill Robinson
This article is part of a series of stories related to cancer advocacy. You can read more articles in the series here.
More than a Game: Super Bowl Initiative Helps Scientists Study the "Normal" Breast
Connie Rufenbarger has always believed that healthy women would willingly donate breast tissue for research if they were convinced the samples could be used to help find a cure for cancer. Now, she has proof: More than 1,800 women have given breast tissue to the Susan G. Komen for the Cure Tissue Bank at the IU (Indiana University) Simon Cancer Center.
Rufenbarger, an advocate for breast cancer research, was instrumental in developing the bank. Its donors have no signs of cancer or breast disease when they provide specimens, making the repository a unique resource for learning about the "normal" breast and how it changes over women's lifetimes.
This weekend, the number of samples in the bank will grow tremendously. Seven hundred women have registered to donate tissue before next month's Super Bowl festivities in Indianapolis. As part of an event billed as Indy's Super Cure, some 600 volunteers will collect tissue, blood, and detailed health histories from the donors.
"The Super Bowl is an incredible opportunity," said Rufenbarger, who has survived breast cancer twice. When the Super Bowl host committee first approached the Komen Tissue Bank about a tissue drive, Rufenbarger envisioned a 1-day event involving 100 donors. But in keeping with the spirit of the Super Bowl, she developed a more ambitious plan.
The Need for Normal Tissue
Experts in the breast cancer field have been discussing the need for normal breast tissue for more than a decade. In 1997, NCI convened an expert panel to identify barriers to progress in preventing and treating breast cancer. The first barrier the panel identified was a "limited understanding of the biology and developmental genetics of the normal mammary gland."
In its report, the panel said that a more complete understanding of the normal breast throughout development—from infancy through adulthood—would be critical to advance the field. Now that the Komen Tissue Bank will have more than 2,000 donors, the staff wants to get the word out to researchers. (Investigators can submit proposals to obtain specimens to study.)
Studying normal breast tissues could reveal early changes that precede breast cancer and could be useful in predicting future risk for the disease. Normal tissue also could be particularly useful for researchers studying cancer prevention, according to Dr. Worta McCaskill-Stevens of NCI's Division of Cancer Prevention.
Prevention researchers have largely relied on breast tissue obtained from patients who were biopsied for clinical reasons or who underwent breast-reduction procedures. Although these tissues may appear benign, they may not be truly normal; the optimal "control" tissue would come from women without breast cancer or other breast lesions, Dr. McCaskill-Stevens noted.
"The ultimate question is: How does normal tissue become malignant?" she added.
Building the Bank
When the idea of a normal breast tissue bank was presented at a 2004 scientific meeting in Indianapolis, some people doubted it could ever happen. Healthy women, they said, would never volunteer to have an invasive procedure that did not offer them a clear benefit, would cause discomfort, and might carry some risk. The regulatory bodies that approve research studies would have to review the plans, they noted, and obtaining approval could be difficult.
Rufenbarger, who attended the meeting, never doubted that women would participate. She and Dr. Anna Maria Storniolo, professor of clinical medicine at the IU School of Medicine, worked closely with ethics experts to develop protocols that allowed women to make an informed decision about donating specimens—initially blood and later blood and breast tissue—for unspecified future research.
Once the IU School of Medicine had carefully reviewed and approved the protocols, women began to donate blood at Komen Race for the Cure events in Indiana and Dallas, and then breast and blood samples at the tissue drives.
Some women have volunteered to donate again, even before walking away from the needle used to collect tissue, noted Dr. Storniolo, who co-directs the tissue bank. "These are women who have ice packs on their breasts as bruises are just beginning to form," she added.
"Critics doubted that women would flock off the street to donate tissue, but they have—at least in Indiana," said co-director Dr. Susan Clare, associate professor of surgery at the IU School of Medicine. She credited advocates like Rufenbarger for making the bank possible.
"Connie just would not let this idea go away," Dr. Clare said. "Breast cancer advocates want this disease to be over. And they want researchers to use this repository and find creative ways to study normal tissue."
Some people have argued that the Komen Tissue Bank may not actually have normal tissue. They have suggested that most donors would be relatives of women who had been diagnosed with breast cancer, and that these donors might themselves be at a higher risk of the disease.
A recent study provided evidence to the contrary. Dr. Amy Degnim of the Mayo Clinic and her colleagues compared three sources of breast tissue that might be considered normal: samples from the Komen Tissue Bank, from women with benign breast disease, and from women who had breast-reduction procedures.
The study showed that the vast majority of tissue sections from the Komen Tissue Bank that were reviewed were histologically normal. The same could not be said for the sections from breast-reduction procedures or benign breast disease. This implies that tissue from the breast-reduction procedures "is probably not a great source of normal tissue in research studies," Dr. Degnim said.
"I would argue that the samples in the bank are the 'real' normal and that these are some of the highest quality breast tissues available," said Dr. Clare. The staff use standardized procedures to obtain the tissue, and samples are frozen within 5 minutes of collection.
Although the majority of donors to the Komen Tissue Bank are Caucasian, the bank has been reaching out to minority populations to increase diversity and make the resource more useful for researchers. Dr. McCaskill-Stevens noted, for example, that members of the Minority-Based Community Clinical Oncology Program, in Cook County, IL, will be participating in the future.
The bank is unique in another way: Four of the donors have developed breast cancer, including one of the very first donors, Traci Runge. (A video about her is online.) "All four women were wise enough to contact us prior to starting treatments," said Dr. Clare. "They asked if we wanted samples of their cancers. These are incredibly precious specimens."
Profiling Normal Tissues
Changing as it does during adolescence, menstrual cycles, nursing, and menopause, the breast may be the most dynamic organ in the human body. The physical definition or molecular profile of a normal breast in each of these stages is still largely unknown, however.
"The poetry here is that normal is not a point; it's a cloud," said Dr. Mark Sherman of NCI's Division of Cancer Epidemiology and Genetics (DCEG), whose team has studied specimens from the Komen Tissue Bank. He noted that testing someone's cholesterol involves comparing results to a range of numbers. "This is just not possible with breast cancer, because there are not any normative values for the molecular features of the normal breast," Dr. Sherman said.
Using specimens from the Komen Tissue Bank and other sources, his group is trying to identify physical characteristics of the breast that could improve risk models for breast cancer.
Some risk factors for developing breast cancer include age, race, prior breast cancer or breast carcinoma in situ, number of first-degree relatives with the disease, age at onset of menstruation, whether a woman has given birth and at what age, and a history of breast biopsies.
"These risk factors have been identified, but we really don't know how the risk factors might be causing changes in the breast," said Dr. Jonine Figueroa, also of DCEG. She is investigating whether physical features of the breast, such as the number and size of lobules, are associated with any of the known breast cancer risk factors.
Dr. Sherman cautions that it is still early days. "The value of defining the morphology and molecular characteristics of the normal breast is unclear," he said. Nonetheless, he is optimistic that understanding how breast cancer risk factors are related to the microscopic appearance and molecular characteristics of the breast could reveal clues to the disease, as well as potential markers of risk.
"We're called mammals because we breastfeed our young," said Dr. Sherman. "Information about the normal breast and how it changes should be part of our basic knowledge about the human body. This is fundamental."
New Partnerships between the Public and Scientists
"This work has to be bigger than breast cancer," said Rufenbarger, noting that everyone who has been involved in the project has been affected by cancer in some way. She believes the project can be a model for developing resources to study other normal tissues that become cancerous, such as the skin.
Dr. Sherman and his colleagues at NCI have already begun to repeat the model by studying other normal tissues, such as the endometrium (the inner lining of the uterus) and the ovary, although these studies use tissues that were removed as part of clinical care.
The Komen Tissue Bank suggests that new partnerships between the public and scientists can expedite the research process, noted Rufenbarger. "The lesson here is that the public is willing and capable of participating in research studies like this one if we can develop a system that allows scientists to tell the public what they need," she said.
Staying Alive: New Technique Grows Normal and Cancer Cells Rapidly
A new technique for rapidly establishing cultures of normal cells and cancer cells from patient tissue samples, and keeping them alive for extended periods of time, could open important new avenues in research and patient care, according to the investigators who developed the culturing method.
In a study published online last month in the American Journal of Pathology, a team of researchers from the Georgetown Lombardi Comprehensive Cancer Center, the National Institute of Allergy and Infectious Diseases, and the Uniformed Services University of the Health Sciences reported a high success rate in establishing the cell cultures, in some cases doing so with as few as four viable cells.
The technique—which relies heavily on a drug called a Rho-associated kinase (ROCK) inhibitor and connective tissue cells called fibroblasts—not only keeps the cells alive and continually reproducing, but initial studies suggest that the cells appear to lack the abnormalities that commonly arise with other cell culturing methods.
Other researchers cautioned that, although the technique holds great promise, it remains to be seen whether other labs can achieve the same results with the method and how closely the cultured cells resemble cells as they exist and function in the body.
At first blush, though, the method "could represent a giant leap for cell culture technology," said Dr. Seema Agarwal of Yale University School of Medicine, who co-authored an editorial on the study.
The cultures have multiple potential uses, said the study's senior author, Dr. Richard Schlegel, chair of the Department of Pathology at Lombardi, such as determining whether patients' tumors are likely to respond to a prescribed treatment. "And as the disease evolves, we would be able to collect and analyze samples at different time points and modulate the treatment depending on the results," he continued.
Although they proposed some possibilities, the research team still needs to better understand the mechanisms by which the technique works, Dr. Schlegel acknowledged. And more sophisticated analyses of cells grown in this manner, including gene expression profiling and mutational analyses, are required to determine more definitively whether the technique fundamentally alters the cells in a way that could limit their use.
"To better understand what is happening will take some time," Dr. Schlegel stressed. "But we thought it was important to get the technique out there."
A Little Bit of This and a Little Bit of That
Human cancer cell lines have been used heavily in research for nearly six decades, dating back to the establishment of the HeLa cell line, as described in Rebecca Skloot's best-selling book The Immortal Life of Henrietta Lacks. But cell lines of some cancer types, such as prostate and lung cancers, have been difficult to establish and often can only be successfully derived from samples of aggressive tumors or metastases, and not from primary tumors, Dr. Schlegel explained. Many cell lines also undergo significant genetic changes during the culturing process.
Cultures of normal, healthy epithelial cells—the cells of origin for the large majority of cancers—are even more difficult to establish, since the cells often quickly become dormant or die. Currently, most success in "immortalizing" normal cells, explained Dr. Channing Der of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, "involves irreversible, sometimes quite drastic, experimental manipulations," such as forcing cells to express the enzyme telomerase or the use of powerful viral oncogenes.
The fibroblasts used in the new culturing method, called feeder cells, are from mice; the ROCK inhibitor is similar to a drug approved in Japan to treat stroke patients. Both have been used previously to establish cell cultures, but this appears to be the first time they have been used together.
Once cells are isolated from tissue samples, they are added to a culture flask containing a layer of feeder cells, along with the ROCK inhibitor and other commonly used components of cell culturing media, and incubated. Every 3 days the feeder cells and the growing epithelial cells are separated and again combined with feeder cells and the ROCK inhibitor.
The researchers call the cells "conditionally reprogrammed cells," Dr. Schlegel explained, because they grow and thrive only under these conditions. If either the feeder cells or the ROCK inhibitor are removed, the cells quickly stop growing.
[This method] could represent a giant leap for cell culture technology.
—Dr. Seema Agarwal
In the reported study, the researchers grew normal cells and cancer cells taken from breast, prostate, pancreas, lung, and colon tumors with varying degrees of success, depending on the tissue type. The group has already improved its success rate, Dr. Schlegel said, by tweaking parts of the process, such as the incubation technique.
The potential to establish immortal normal cell and tumor cell cultures from the same patient "would be a powerful advance that we haven't had before," said Dr. Der.
For example, because screening finds a growing number of cancers at earlier stages, Dr. Agarwal noted, having matched normal cell and tumor cell cultures from the same patient could provide valuable insight into the initial stages of cancer development—research that has been extremely difficult to do.
"That is largely a black box for us right now," she said. "It could open up things about the biology of cancer that we don't understand yet."
There is still "a long way to go" to better understand the potential use of cell cultures established in this manner, Dr. Der cautioned. The ROCK inhibitor used in the study, for example, is not a "pure" ROCK inhibitor, he noted. It targets several other kinases, so the impact of the drug's more promiscuous activity has to be more clearly explained. Studies are also needed to analyze whether the mouse fibroblasts are causing unanticipated changes in the growing human cells at the genomic and protein levels, stressed Dr. Agarwal, who recently learned the technique at Lombardi.
The culturing process should also be tried with human fibroblasts as feeder cells as a validation step, she continued, "and if there is a difference [in the results], it raises a concern about whether the microenvironment niche created by using the mouse feeder layers is indeed different than the human microenvironment."
More studies are needed to determine the technique's impact on the epigenetic makeup of the cultured cells and whether the technique has the same effect on the expression of an important tumor suppressor gene, called p16, that is frequently altered in another common culturing technique, said Dr. Bernard Weissman, also of the UNC Lineberger Cancer Center.
Although there are still many unknowns, if the technique can be validated and refined by other labs, it "clearly has some big advantages" over current culturing methods, Dr. Weissman said. "We would have far more robust [in vitro] models than we currently do," he added, which could improve our understanding of the biology of cancer development and progression. "That's where I think this will have a big impact."
A Closer Look
Targeted Therapies Offer Treatment Options for Advanced Kidney Cancer
For decades, oncologists had little reason to be optimistic about treating patients with advanced kidney cancer. But over the past 15 years, important discoveries have produced targeted therapies to treat cancer that has spread beyond the kidney (metastatic disease) and offer new directions for developing even more effective treatments.
"When we first started working on kidney cancer in the early 1980s, it was thought of as a single disease, and all kidney cancers were treated the same," said Dr. W. Marston Linehan, chief of the NCI's Urologic Oncology Branch.
Then, as now, surgery was the first treatment for renal cell carcinoma (RCC), the most common type of kidney cancer, which had not spread. Once the cancer had metastasized, however, patients generally had a poor prognosis and most did not survive more than a year.
"Kidney cancer was thought to be this disease that inexorably led to death," said Dr. George Philips, a researcher at Georgetown Lombardi Comprehensive Cancer Center.
Because traditional chemotherapy is not effective in kidney cancer, Dr. Philips continued, patients with advanced disease were treated with cytokines, either interleukin-2 or interferon alpha, both of which have considerable toxic side effects. Only 5 to 10 percent of patients treated with high-dose interleukin-2 experienced a complete and lasting response.
To try to improve conditions for these patients, Dr. Linehan and his colleagues from across the National Institutes of Health (NIH) began recruiting families that had multiple members with kidney cancer. "We wanted to identify what we thought was the gene for kidney cancer," said Dr. Linehan. "Our hope was, if we could understand the gene that causes kidney cancer, that [understanding] could possibly provide the foundation for developing a targeted therapeutic approach."
Ten years later, the researchers identified mutations in a gene called VHL in patients with von Hippel-Lindau syndrome, a hereditary cancer syndrome in which patients develop kidney tumors with a specific histology, or cellular organization, known as clear cell RCC. They subsequently determined that the VHL gene was also mutated or silenced in most non-hereditary clear cell RCCs, suggesting that VHL was the kidney cancer gene they were seeking.
This discovery led researchers to test therapies that target the VHL pathway, and today there are six drugs approved by the Food and Drug Administration to treat patients with advanced clear cell RCC: vascular endothelial growth factor (VEGF) receptor inhibitors (sorafenib, sunitinib, and pazopanib); a VEGF-binding antibody (bevacizumab); and inhibitors of the mTOR pathway (temsirolimus and everolimus), another VEGF regulator. Although many patients benefit significantly from these agents, few patients are cured.
Multiple Genes, Multiple Diseases
Nearly three-quarters of RCC tumors have clear cell histology. The rest, however, display a variety of other histologic patterns. To evaluate the genetic basis of these rarer cancers, Dr. Linehan and his colleagues studied families with non-clear cell RCC. From some of these families they identified a new form of kidney cancer, called hereditary papillary renal carcinoma (HPRC).
Families with HPRC did not have the clinical characteristics of von Hippel-Lindau syndrome, nor did they have VHL gene mutations. Instead, the researchers identified mutations in the proto-oncogene MET, and showed for the first time that a different gene could cause a different type of kidney cancer.
The team wondered if this was a fluke, or if other RCC histologic types were associated with mutations in additional genes. When they examined families with Birt-Hogg-Dubé, a syndrome characterized by multiple skin lesions, the researchers determined that these patients developed chromophobe and oncocytic RCCs. Unlike the clear cell and papillary tumors, these tumors had alterations in a new gene that the group named FLCN.
In addition, another research group found that patients with hereditary leiomyomatosis RCC, a very aggressive form of kidney cancer that Dr. Linehan's group had been studying since the late 1980s, have mutations in fumarate hydratase, an enzyme that plays an essential role in the metabolic process that cells use to generate energy from glucose. To date, investigators have identified 15 different genes that cause distinct types of kidney cancer.
"Today we know that kidney cancer is not a single disease," commented Dr. Linehan. "It's made up of a number of different types of cancer, each with a different histologic type, with a different clinical course, responding differently to therapy, and caused by [mutations in] different genes. But each of these genes is fundamentally involved in the same pathway: the cell's ability to sense oxygen, iron, nutrients, or energy. We have concluded that kidney cancer is fundamentally a metabolic disease."
The Search for More Effective Treatments
Since as many as 20 percent of newly diagnosed patients will have metastatic disease, researchers are far from where they want to be, even with the well-studied clear cell type of RCC, commented Dr. Michael Atkins, leader of the Kidney Cancer Program at the Dana-Farber/Harvard Cancer Center. "We want to produce durable responses in the majority of patients," he said.
To improve patient outcomes, current studies are examining which treatment a patient should receive first based on the characteristics of his or her tumor, the optimal doses and schedules for current treatments, and the best sequence to use for available therapies. Because these tumors are highly vascular, imaging techniques, such as functional magnetic resonance imaging (fMRI) or positron emission tomography (PET), may allow researchers to observe subtle treatment effects and modify treatment accordingly.
Other groups, Dr. Atkins continued, are developing more selective inhibitors of the VEGF receptor. These more selective agents may allow clinicians to combine therapies to produce synergistic tumor-fighting activity while sparing patients the side effects associated with less-selective agents. The limited success of cytokine therapy, which activates the immune system, has prompted researchers to investigate the use of novel, more potent immunotherapies.
Researchers are also trying to tease out the pathways tumors use to resist current therapies in order to develop new drugs that target these pathways. Likewise, discovery of the genes that regulate the non-clear cell RCC subtypes has provided numerous potential drug targets. For example, Dr. Linehan's group is conducting trials of agents targeting fumarate hydratase.
Investigators may need to change the design of clinical trials to study the less-common non-clear cell cancers and to evaluate overall survival differences for all RCC therapies more stringently. Additionally, programs such as The Cancer Genome Atlas continue to look for new genes and pathways that regulate RCC, with the aim of developing novel therapy targets.
"I think there has been enormous progress made in kidney cancer," said Dr. Linehan. "Do we need to do better? Of course! But I am very encouraged about the future."
Featured Clinical Trial
First-in-Humans Study of New Immunotherapy Agent
Name of the Trial
Phase I Study of Intravenous Recombinant Human IL-15 in Adults with Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer (NCI-10-C-0021). See the protocol summary.
Dr. Thomas Waldmann and Dr. Kevin Conlon (Associate Investigator), NCI Center for Cancer Research
Why This Trial Is Important
The goal of cancer immunotherapy is to stimulate or restore the immune system's ability to attack cancer cells. Although some evaluated treatments have demonstrated an ability to help boost or activate immune responses against cancer cells, immunotherapy is still a relatively new area of cancer research and much remains to be learned. For example, researchers need to learn how best to incorporate immunotherapy into cancer treatment strategies, which cancers are most susceptible to immune system manipulation, and how to reduce or avoid serious side effects.
The immunotherapy agent interleukin-2 (also called IL-2 or aldesleukin) has been approved by the FDA for the treatment of metastatic melanoma and metastatic renal cell carcinoma, the most common type of kidney cancer. IL-2 is a type of cytokine, a naturally occurring protein that helps regulate immune responses.
Despite its anticancer activity in some patients, IL-2 therapy has several drawbacks. IL-2 plays a dual role in the immune system by stimulating the proliferation of cells that can attack and kill pathogens (including cancer cells), and suppressing immune responses to keep the immune system from attacking the body's normal cells (autoimmune responses). As a result, IL-2's stimulation of cancer-killing cells, such as cytotoxic T cells and natural killer cells, fades rather quickly, necessitating the use of high doses of IL-2 to be effective.
But, high doses of IL-2 often produce serious side effects that may adversely affect a patient's quality of life, compromise treatment, or even result in the patient's death. Therefore, doctors are eager to identify other immunotherapy agents that provide benefits similar to IL-2 but with fewer drawbacks.
Another member of the interleukin family, interleukin 15 (IL-15), may be one possibility. In preclinical studies, IL-15 has been shown to stimulate many of the same immune cells as IL-2 but with much longer-lasting effects. Unlike IL-2, it does not act to suppress immune responses. IL-15 also stimulates the proliferation of immune cells that have a "memory" of the cancer, so the immune system can recognize and attack the cancer again, possibly enabling it to head off recurrences. Furthermore, animal studies with IL-15 suggest that it may also have a better side effect profile than IL-2.
"Both IL-2 and IL-15 stimulate T cells and B cells, and they are involved in the generation of natural killer cells, but they are clearly different," said Dr. Waldmann, who co-discovered IL-15 in 1994. IL-2 suppresses T-cell immune responses to prevent autoimmunity, explained Dr. Waldmann. IL-15, in contrast, produces an immune response of very long duration, he continued.
"In studies with nonhuman primates, we've seen natural killer cells increase sevenfold and cytotoxic T cells increase 80- to 100-fold following administration of IL-15 as a 10-day continuous infusion. So [in IL-15] we have an agent that is a superstimulator of natural killer cells and cytotoxic T cells," he explained.
Laboratory and animal testing with IL-15 has generated a great deal of interest in bringing the agent to clinical testing in cancer patients. In fact, immunotherapy experts participating in the NCI Immunotherapy Agent Workshop in 2007 ranked IL-15 as the most important agent to bring to clinical trials.
"Researchers have been waiting a long time for clinical grade IL-15, but pharmaceutical companies have largely gotten out of the business of producing new cytokines following some early clinical disappointments [with immunotherapy]," said Dr. Conlon. "So, NCI has invested in developing and producing the agent through its Developmental Therapeutics Program to allow clinical testing of this very highly anticipated cytokine to proceed."
In this first-in-humans study of IL-15, patients with metastatic melanoma or metastatic renal cell cancer who have not benefited from other therapies will be given IL-15 by intravenous injection once a day for 12 days. Doctors will assess the tolerability of IL-15 therapy in the patients and determine the maximum tolerated dose and dose-limiting toxicities.
"We're currently in the process of planning additional studies of IL-15, using different routes of administration so that we can better inform future phase II monotherapy and combination studies to be conducted through the new Cancer Immunotherapy Trials Network and by other extramural and intramural researchers," Dr. Conlon added.
Glucarpidase Approved to Lower Toxic Chemotherapy Levels in the Blood
The kidneys usually eliminate methotrexate from the body, but patients receiving high doses of methotrexate can develop kidney failure. Glucarpidase is an enzyme that rapidly breaks down methotrexate into a nontoxic form that can be eliminated from the body more rapidly.
“Prolonged exposure to high levels of methotrexate can result in kidney and liver damage, severe mouth sores, damage to the lining of the intestine, skin rashes, and death due to low blood counts,” explained Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a news release.
Glucarpidase is designated an orphan drug, a designation given to therapies for diseases or conditions that affect fewer than 200,000 people in the United States.
In a clinical study of 22 patients, treatment with intravenous glucarpidase was effective in 10 patients—that is, patients’ methotrexate levels fell below a critical level within 15 minutes and stayed below that level for 8 days. (Methotrexate levels were analyzed at NCI using a sensitive and specific test.) Although not all patients experienced this result, glucarpidase eliminated 95 percent of the methotrexate in all patients.
A separate clinical study evaluated the safety of glucarpidase in 290 patients experiencing problems clearing methotrexate from their blood. The most common side effects observed in the study were low blood pressure, headache, nausea, vomiting, flushing, and abnormal skin sensation (paresthesia).
Most of these patients were enrolled in a compassionate-use trial run by NCI’s Cancer Therapy Evaluation Program. The trial showed that glucarpidase was well tolerated and resulted in a rapid and profound decrease in methotrexate concentrations in the blood.
New Warnings Added for Lymphoma Drug
The Food and Drug Administration (FDA) has added a boxed warning for the lymphoma drug brentuximab vedotin (Adcetris) highlighting the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious viral infection of the brain that can result in death. The agency has also added a new contraindication warning against the use of brentuximab vedotin with the cancer drug bleomycin due to increased risk of lung toxicity, characterized by cough or shortness of breath.
The FDA approved brentuximab vedotin for patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma in August 2011. The treatment combines a drug with an antibody that directs the drug to a target on lymphoma cells. At the time of the drug’s approval, one case of PML was described in the drug’s safety information. In a drug safety communication issued January 13, the FDA alerted the public to two additional cases of PML.
The signs and symptoms of PML can develop over several weeks or months. They may include changes in mood or in usual behavior; confusion; thinking problems; loss of memory; changes in vision, speech, or walking; and decreased strength or weakness on one side of the body. Patients who develop any signs or symptoms of PML should notify their health care professional immediately. Brentuximab vedotin treatment should be suspended if PML is suspected and discontinued if PML is confirmed.
Patients and health care professionals should report serious side effects from the use of brentuximab vedotin, including confirmed cases of PML, to the FDA MedWatch program online or by calling 1-800-332-1088.
NIH and Industry Create "Living Lab" to Study Molecular Structures and Disease
The National Institutes of Health (NIH) and FEI, a scientific instruments company based in Hillsboro, OR, have created the Living Lab Structural Biology Center, a public-private partnership that will use near-atomic resolution microscopy and other technologies to investigate molecular structures that play a role in cancer and other diseases.
The lab, located on the NIH campus in Bethesda, MD, is an interdisciplinary collaboration involving experts from FEI, NCI, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in the fields of cryo-electron microscopy, nuclear magnetic resonance spectroscopy, x-ray diffraction, and biochemistry. A Titan Krios transmission electron microscope, one of the world's most powerful electron microscopes available commercially, will be located at NIH to enable the collaborative research.
This research effort will develop methods and workflows, from sample preparation through data analysis, that combine information from all of the technologies in the Living Lab. Scientists have historically relied on nuclear magnetic resonance and x-ray diffraction techniques to determine the structures of molecular complexes and proteins that play a role in various diseases. These methods have limitations, however. Cryo-electron microscopy provides near-atomic resolution without requiring crystallization of samples or limiting molecular size and complexity, as other techniques do.
"Technical advances make it possible to tackle extraordinarily challenging problems," said Dr. Robert Wiltrout, director of NCI's Center for Cancer Research, in a news release. "Successful integration of cryo-electron microscopy, x-ray diffraction, and nuclear magnetic resonance results could accelerate discovery of biological mechanisms and provide powerful tools to assist drug design."
Dr. Sriram Subramaniam, a senior investigator in NCI's Laboratory of Cell Biology, directs the Living Lab. "The prospects for applying cryo-electron microscopy to study the structures of a broad spectrum of medically relevant complexes have changed dramatically in recent years with advances in microscope hardware and powerful new methods for image analysis," Dr. Subramaniam said in a news release.
CURE Report Focuses on Reducing Disparities in the Cancer Workforce
NCI's Center to Reduce Cancer Health Disparities has released a new monograph—The CURE Paradigm: Enhancing Workforce Diversity. The Continuing Umbrella of Research Experiences (CURE) program, launched in 1997, is a national research training and career development effort aimed at building and sustaining a pipeline of competitive cancer investigators from groups typically underrepresented in biomedical science and cancer research.
The monograph traces CURE's goals, its 15-year history, the training and career development opportunities available to trainees and students, the program's achievements to date, and its projected future. The monograph highlights five CURE trainees who describe how the program has enabled them to pursue cancer and health disparities research careers.
CURE is the first National Institutes of Health program to offer long-term support to qualified, underrepresented students and professionals who are at risk of being lost from the training pipeline. Starting with individuals as young as high school students and extending up to newly funded, independent, and competitive cancer researchers, CURE trains people from racially and ethnically diverse backgrounds underrepresented in cancer research to help ensure a diverse workforce for the future.