National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 30, 2009 • Volume 6 / Number 13

Page Options

  • Print This Document
  • Email This Document

The information and links on this page are no longer being updated and are provided for reference purposes only.

NEWS

Watch the video of President Barack Obama signing the Family Smoking Prevention and Tobacco Control Act on June 22

FDA Will Regulate Tobacco Under New Law

Calling it a bill that "will save American lives," President Obama has signed into law the Family Smoking Prevention and Tobacco Control Act, which grants the Food and Drug Administration (FDA) the authority to regulate tobacco products. Under the law, the FDA now has sweeping new authorities related to the manufacture, marketing, and sale of tobacco products—authorities covered by a more expansive public health standard than has traditionally been granted to the agency. Read more > >

COMMENTARY

Director's Update: Putting Some Perspective on Research and Risk

For as long as there has been a National Cancer Institute, its leaders have attempted to strike a delicate balance between the potentially huge payoffs of risk-taking science and the benefits of more measured progress that comes from incremental research. It is, I believe, a healthy tension that should always be part of discovery--perhaps most importantly when it involves our work on a disease such as cancer. The work we do in our laboratories, we always hope, can eventually be used to help our patients. To me, that puts each experiment I plan in my lab in a different light. Read more > >

Guest Commentary by Dr. Jeanette Vega: Chile and the United States—Forming a Proud Partnership

The Republic of Chile's Undersecretary of Public Health shares her thoughts on the collaborative efforts between our two countries in a number of important research areas, including basic and clinical cancer research, bioinformatics, and training and resource sharing. Read more > >

IN DEPTH

UPDATES

  • Notes

    • Dr. Diane Meier Participates in White House Health Reform Stakeholder Discussion
    • NCI Scientists Featured in Journal of Minority Medical Students
    • caBIG Annual Meeting Slated for July
    • BSA Meeting Held

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

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

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

Featured Article

FDA Will Regulate Tobacco Under New Law

Calling it a bill that “will save American lives,” President Barack Obama signed into law the Family Smoking Prevention and Tobacco Control Act, which grants the Food and Drug Administration (FDA) the authority to regulate tobacco products. Under the law, the FDA now has sweeping new authorities related to the manufacture, marketing, and sale of tobacco products—authorities covered by a more expansive public health standard than has traditionally been granted to the agency.

  

President Barack Obama signed the Family Smoking Prevention and Tobacco Control Act on June 22.

Enactment of the law was met with praise by members of Congress and many officials from the nation’s top public health and medical organizations, hundreds of which had endorsed the legislation.

“Today is a day for special celebration as President Obama signs into law this long-overdue authority for FDA to regulate tobacco products,” stated Senator Edward Kennedy (D-MA), the primary sponsor of the bill in the Senate and an ardent backer of efforts to regulate tobacco.

The push by some lawmakers and public health organizations to grant the FDA legal authority over tobacco products began in earnest in the mid-1990s. It took on renewed vigor, however, following a 5-4 decision by the U.S. Supreme Court in the spring of 2000, in which the court ruled that the FDA did not have the authority to regulate tobacco and that Congressional action would be required to grant the agency that power.

The new law does just that, providing the FDA with a comprehensive array of legal authorities. For example, it requires:

  • New, larger, more prominent warning labels on tobacco products about potential harms and ingredients, and a prohibition on the use of misleading terms such as “light” or “mild”
  • Significant restrictions on marketing geared toward teenagers and children, including restricting advertising to black-and-white text in stores and in magazines with high teen readership, and a complete ban on tobacco sponsorship of sports and entertainment events
  • Tobacco product manufacturers to register with the agency every 2 years and submit to the agency comprehensive information about the manufacture and composition of all tobacco products they wish to market, including pre-market review of any new products
  • A ban on candy-like flavorings and certain other additives to cigarettes

Under the new law, the agency’s approach to regulation would not follow the “safe and effective” standard employed for drugs and other items over which the FDA has regulatory control, explained Mitch Zeller, vice president for policy and strategic communications at Pinney Associates in Washington, DC, who directed the FDA’s Office of Tobacco Programs in the 1990s. Rather, its regulatory activities for tobacco will be guided by a standard of what is appropriate for the protection of the public's health.

“It’s a very broad standard,” Zeller continued. “Congress elucidates what that standard means when it comes to regulatory functions such as … proposed product standards that the agency would issue.”

That legal flexibility is very important, said Vince Willmore from the Campaign for Tobacco Free Kids. It means the FDA “won’t have to go to Congress every time it needs to take additional steps to protect public health” with regard to tobacco, he added.

“We think this is the strongest tobacco control measure that Congress has ever approved,” Willmore said.

The law also establishes a mechanism to fund the FDA’s tobacco regulation activities by levying fees on manufacturers and importers of tobacco products. It also mandates the formation of a new Center for Tobacco Products within the FDA, as well as a Tobacco Products Scientific Advisory Committee to, among other things, help guide the implementation of the new law.

There's a New Law—Now What?

The FDA will now begin the process of hiring staff and creating the infrastructure for the Center for Tobacco Products at FDA, which, said Zeller, will likely be as large as the agency’s centers for biologics and devices. As far as regulatory actions are concerned, explained Willmore, the law contains specific deadlines for certain actions.

They include issuing regulations that will:

  • Within 3 months, ban candy, fruit, and other flavors from cigarettes
  • Within 12 months, ban product labels using terms such as “light” and “low tar”
  • Within 15 months, restrict the marketing and sale of tobacco products to teens and children; this includes restricting advertising to black-and-white text in stores and in magazines with high teen readership
  • Within 24 months, require larger, graphic warning labels

In the case of nicotine, Zeller noted, although the FDA is prohibited under the law from requiring that nicotine be eliminated from tobacco products, there is nothing in the law that prevents the agency from requiring nicotine levels that fall below the threshold for addiction—something, he added, that is currently the topic of ongoing research.

Zeller said that the first FDA actions under the new law will focus on restrictions on sales and marketing of tobacco products to teenagers and children. (See box above.) The agency may also look to a guidance document issued last year by the World Health Organization that identifies priority areas for tobacco regulation.

While FDA regulation is expected to help make dramatic strides in reducing the nation’s prevalence of tobacco use, it is not a panacea, said Dr. Cathy Backinger, chief of NCI’s Tobacco Control Research Branch. “Regulation is a critical component of a comprehensive tobacco control agenda, but it is not the only thing we need to do to make progress,” she said. “We also need to implement evidence-based programs and policies and continue research efforts to understand how to drive down both youth and adult tobacco-use prevalence.”

—Carmen Phillips

ALSO OF INTEREST

Research Supporting Regulation

An important component of the FDA’s regulation of tobacco products will be research into a number of important scientific issues that affect how the agency conducts its work, said NCI officials. “Research supported by NCI and other NIH and federal health agencies will be very important to inform the agency’s efforts with regard to tobacco,” explained Dr. Backinger. “We look forward to working with the FDA to ensure that the science base for regulation expands to meet their needs.”

NCI-funded tobacco control research includes multidisciplinary studies of potential reduced-exposure tobacco products, both smoked and smokeless; research to analyze tobacco industry documents to better understand the industry’s knowledge, strategies, and tactics; research on the determinants of tobacco use and addiction; and studies to identify strategies to prevent and reduce tobacco use. To learn more about NCI-funded research supporting tobacco regulation, visit: http://dccps.nci.nih.gov/tcrb/research_topic-tob_products.html and http://dccps.nci.nih.gov/tcrb/research_topic-tob_industry.html.

RESOURCES

A Resource for Tobacco Prevention Policy and Research

Earlier this month, the Robert Wood Johnson Foundation released Cigarette Smoking Prevalence and Policies in 50 States: An Era of Change, an extensive analysis of tobacco prevention and control strategies from across the country and an examination of current tobacco usage patterns based on the NCI-sponsored Tobacco Use Supplement to the Current Population Survey. The report presents state and national data on tobacco prevalence, policies implemented to diminish that prevalence, and programs and policies to help smokers quit.

Cancer Research Highlights

For Children with Leukemia, Radiation May Be Unnecessary

Children with the most common form of leukemia can safely forego radiation therapy to prevent a relapse of the disease if they are treated with chemotherapy regimens tailored to their individual needs. This is the conclusion of a clinical trial involving 498 patients with acute lymphoblastic leukemia (ALL). Nearly 94 percent of the patients were still alive 5 years after treatment, a result that compares favorably with other ALL treatment studies.

The strategies and treatments employed in this trial could be adopted by other medical centers, said researchers from St. Jude Children’s Research Hospital in Memphis, who published their results in the June 25 New England Journal of Medicine.

Cranial irradiation has been used since the 1960s as a way to prevent a recurrence of cancer in the brain. First introduced by researchers at St. Jude, it was considered a breakthrough and improved survival rates in the disease to about 50 percent. Thanks to continued improvements in chemotherapy, today 90 percent of children with ALL are cured of their disease.

But with a growing population of survivors and clear evidence that radiation exposure can lead to second cancers and cognitive problems, many centers have limited its use to patients at risk of a relapse. In the trial, Dr. Ching-Hon Pui and his colleagues tailored chemotherapy regimens for each patient and used the latest techniques for delivering the drugs and monitoring their effectiveness. After several weeks, adjustments could be made if a patient had evidence of residual cancer cells.

Based in part on comparisons with historical data on patients with ALL, the researchers conclude that individualized chemotherapy regimens are preferred over treatments that include cranial irradiation. They even recommend against irradiation for patients considered at risk of relapse. If this group had received radiation therapy in the current study, the researchers explained, 90 percent of the patients would have received radiation unnecessarily.

“The introduction of radiation therapy in the 1960s put the word ‘cure’ into discussions of ALL,” said coauthor and director of St. Jude, Dr. William Evans. “The importance of the current study is that we’re now removing radiation from the therapy. And the reason we’re able to do this is that we’ve gotten smarter and better at using chemotherapy.”

Survivors of Hodgkin Lymphoma May Face Increased Risk of Stroke

Patients who receive radiation therapy for Hodgkin lymphoma may be at increased risk of a stroke or transient ischemic attack (TIA), also called a “mini stroke,” later in life, according to a report in the July 1 Journal of the National Cancer Institute. The risk is primarily associated with radiation to the neck and chest area, and it remains elevated for years after treatment.

The researchers, led by Dr. Flora E. van Leeuwen of the Netherlands Cancer Institute, tracked 2,201 survivors of Hodgkin lymphoma who were treated before the age of 51 between 1965 and 1995. At a median follow-up of almost 18 years, 96 survivors developed a stroke or TIA. The incidence of stroke among the survivors was 2.2 times that of the general population, while the incidence of TIA was 3.1 times that of the general population.

Overall, these events occurred at a relatively young age (the median age was 52 years, with a range from 24 to 80 years). For young survivors of Hodgkin lymphoma who are at especially increased risk of stroke and TIA, physicians should consider strategies to reduce the risk, such as treatment of hypertension and certain lifestyle changes, the researchers said.

The findings add to the overwhelming evidence that using radiation therapy in Hodgkin lymphoma is “shortsighted,” according to an accompanying editorial by Dr. Dan Longo of the National Institute on Aging. Even though treatments for this disease have included reduced doses of radiation since 1995, there is no evidence yet that this translates into fewer late effects for survivors, he cautioned.

“Unfortunately, given the lifelong increased risks of late effects that have been documented from the use of radiation therapy, we simply cannot keep exposing patients to risk without clear benefit while we wait for safety data to be produced,” Dr. Longo added.

Another Genetic Change Linked to Neuroblastoma: Missing DNA

A series of genome studies have, for the first time, revealed common genetic changes associated with neuroblastoma, a cancer that most often occurs in children. Building on this work, researchers have now expanded the scope of these surveys to include structural changes, such as gains and losses of DNA. As reported in the June 18 Nature, this strategy has revealed a region of chromosome 1 that is missing in some children with neuroblastoma and that may contribute to their disease.

Gains and losses of DNA, known as copy number variations or CNVs, have been linked to conditions such as autism and schizophrenia, but this study is the first to demonstrate their role in predisposing to cancer. Dr. John Maris of the Children’s Hospital of Philadelphia and his colleagues made the discovery by screening DNA from 1,600 children with and without the disease. The missing DNA on chromosome 1 was confirmed in two independent groups, and additional evidence for its role in neuroblastoma came from experiments in cells.

Neuroblastoma arises in children in the developing cells of the sympathetic nervous system. The unstable region of chromosome 1 is near a family of genes involved in the development of the central nervous system. In experiments with cells, the researchers learned that the CNV alters the activity of a previously unknown member of this gene family, which resides within the region. The presence of this CNV alone is not sufficient to cause neuroblastoma, the researchers noted.

Indeed, a variety of genetic alterations contribute to the disease, including, it now appears, CNVs. In their previous studies (here, here, and here), Dr. Maris and his colleagues in the Children’s Oncology Group implicated two other types of genetic changes—mutations and single nucleotide polymorphisms (SNPs), which are places in the genome where a single letter of DNA may vary from person to person.

“It has been widely thought that CNVs could play a role in cancer, but the evidence has been lacking,” said Dr. Sharon Diskin of the Children’s Hospital of Philadelphia, the first author of the new study. “We hope that our findings provide the evidence for the importance of expanding genome-wide association studies to include CNVs as well as SNPs in cancer.”

Immune Cells with Stem Cell-like Properties Destroy Tumors in Mice

Researchers from NCI’s Center for Cancer Research have shown that a cell signaling network called the Wnt-β-catenin pathway drives the development of a type of immune cell that may provide opportunities to enhance cancer immunotherapies. Immunotherapy techniques recruit the body’s immune system to attack cancer cells.

In a paper published online June 14 in Nature Medicine, the researchers found that when T cells—a type of white blood cell—were cultured with drugs that mimic components of the Wnt pathway, the T cells acquired stem-cell like properties. They were able to both regenerate themselves and produce daughter cells that differentiated into mature T cells, which can recognize and attack cancer cells.

These cells, called CD8+ memory stem cells, were tested as a treatment for large melanoma tumors (containing about one billion malignant cells) in mice. Relatively tiny numbers (about 40,000) of these T cells given in combination with a tumor vaccine and an immune system stimulant called interleukin 2 were able to trigger the destruction of the bulky tumors and improve survival. The memory stem cells that were transplanted multiplied 10 to 30 times more than other types of T cells tested in the mice.

“This new category of lymphocytes is superior to T cells used in earlier experiments because they have the enhanced ability to renew themselves, to proliferate, to differentiate and ultimately to kill tumor cells,” said lead author Dr. Nicholas Restifo in a statement.

Adoptive immunotherapy, the reinfusion of anti-tumor T cells after expansion outside the body, has shown promise as one of the few new therapies that may result in complete remission for patients with metastatic disease. This approach has previously relied on the transfer of large numbers of tumor-specific T cells generated and expanded in the laboratory, a time-consuming and expensive process. However, the use of smaller numbers of “stem-like” T cells may broaden the use of this treatment approach in patients with cancer, said Dr. Restifo. Further studies are needed to confirm the promising results from CD8+ memory stem cells in humans, concluded the authors.

Director's Update

Putting Some Perspective on Research and Risk

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

For as long as there has been a National Cancer Institute, its leaders have attempted to strike a delicate balance between the potentially huge payoffs of risk-taking science and the benefits of more measured progress that comes from incremental research. It is, I believe, a healthy tension that should always be part of discovery—perhaps most importantly when it involves our work on a disease such as cancer. The work we do in our laboratories, we always hope, can eventually be used to help our patients. To me, that puts each experiment I plan in my lab in a different light.

This past Sunday, an article on the front page of The New York Times, “Grant System Leads Cancer Researchers to Play It Safe,” argued that our sense of balance has become skewed. Writer Gina Kolata posited that grants awarded by NCI—and the American Cancer Society and other organizations, as well—have become “a way to keep research laboratories going year after year with the understanding that the focus will be on small projects unlikely to take significant steps toward curing cancer.”

“The institute’s reviewers,” she continued, “choose such projects because, with too little money to finance most proposals, they are timid about taking chances on ones that might not succeed.”

Ms. Kolata’s arguments are not especially new. Around the world, many different systems have been designed to provide financial support to scientists. I dare say, despite its weaknesses and perceived faults, the NIH peer-review system remains the envy of the world—and one of the most duplicated.

Despite the high regard for our grant support structure, NIH, in an effort to continue to refine and better the system, last year released a report and an implementation plan for improving peer review. This year-long process sought input from every corner of the research community to examine the review system and address longstanding concerns that the process was too slow and biased against innovation and clinical research. Knowing the NIH system as a grantee, reviewer, and now institute director, I am particularly disappointed in the Times story. As I stressed to Ms. Kolata in a lengthy interview, an accurate account of how cancer funding priorities are set cannot be expressed in just a few simple phrases. It is a story of nuance and of leadership in moments of change, evolving technology, and scientific opportunity. Research, by its very nature, is always about new ideas, creativity, and hope.

From 2004 to 2008, as NCI’s budget increases hovered below the rate of biomedical inflation, most investigators wisely chose to put their best science forward in their R01 grant proposals, and they found other ways to generate resources for higher-risk, higher-reward projects. This is no more than simple logic. In turn, as riskier efforts mature, those that prove worthy tend to work their way into one’s principal grants. In other words, I suggested in the interview, scientists are not more risk-averse today; they are simply more careful about where they place risk.

Importantly, NCI counts on its division and center leaders to carefully study all grants that have received peer-review scores. NCI routinely searches through every grant that is above the year’s payline in order to fund exciting, innovative projects—and, yes, even risky applications—with potential value. For example, in fiscal year 2008, NCI used approximately $80 million to fund such innovative exceptions for grants that were above the payline. Likewise, each September, I personally review all new investigator grants that have not been funded to make sure we support as much worthy and innovative science as we have applications for, even if they fall outside the cutoff scores assigned by peer review.

What is the evidence that NCI places a high priority on high-risk, innovative science? Perhaps the answer can be found in the growing number of NCI grantees who receive national and international recognition for research excellence. Just last week, Dr. Chad Mirkin of Northwestern University was named the 2009 winner of the $500,000 Lemelson-MIT Prize, which is sometimes referred to as the “Oscar for inventors.” Dr. Mirkin is an NCI-funded investigator, as is Dr. Joseph DeSimone from the University of North Carolina, who won that same award last year. Also last week, two Stanford University graduate students won the inaugural IEEE Presidents’ Change the World Competition. Their work is also sponsored by NCI. Over the years, there have been 39 Nobel laureates who have been supported by NCI.

“Well, that is great,” you might say, “but what about making a difference for patients?” I think it’s important to remember that ingenuity, coupled with persistence, is almost always the hallmark of NCI-supported clinical research. Take for example Dr. Michael R. Grever from Ohio State University, an NCI grantee who is conducting early phase trials with a drug called flavopiridol. The drug was abandoned by industry because of potentially lethal toxicity, but Dr. Grever persisted in his belief that flavopiridol had potential benefits for cancer patients if the toxicities could be overcome. This clinical research is showing strongly positive results in chronic lymphocytic leukemia patients. There are many more such stories, including work on immunotoxins and re-engineered T cells to clear patients of advanced melanoma.

In my interview for the Times story, I suggested to Ms. Kolata that the very nature of cancer science is beginning to undergo fundamental change and that not all scientific risk takes place in the realm of the classic R01 or similar grants. Consider, if you will, our initiatives in cataloguing the cancer genome, which are in fact the next generation of a project once deemed highly risky by the scientific community. The Cancer Genome Atlas will increasingly require competitively awarded, task-driven science conducted by teams of researchers in order to understand the biologic function of genetic alterations associated with cancer that can be targeted by new therapeutic interventions. A sure thing? Certainly not. If we are to succeed, though, the road to new interventions, to new methods of individual prevention, and to the earliest detection, will require scientists to work as a team. Clearly, it is a different view of risk and reward.

In the months and years ahead, we will witness innovative, creative science in new centers of excellence like NCI’s forthcoming Physical Science-Oncology Centers, where physicists, chemists, mathematicians, and biologists will come together to develop entirely new perspectives on the physical forces involved in cancer. (Notably, 7 Nobel laureates either applied for or helped review this program, and 24 National Academy of Science members and 9 National Academy of Engineering members were included in the groups that applied to form centers.) My take is that this is certainly not business as usual.

We will also watch the progress of our existing programs in nanotechnology research, proteomics, and molecular analysis—all cutting-edge projects that will in turn, because of their boldness, benefit the entire research community. When NCI began each of these initiatives over 6 years ago, there were many critics.

To be sure, transformative science will still happen in individual laboratories. NCI will continue to foster aggressive programs to train and support young investigators, whose new ideas will fuel the field for years to come. Those of us running active laboratories commonly acknowledge that the creativity and surprise discoveries most often come from the young people in our labs—students and fellows—and that is how it should be.

We will look to our Specialized Programs of Research Excellence (SPOREs) for new knowledge and its translation to the clinic. We will closely watch the recipients of the Challenge Grants and Grand Opportunities grants made possible by economic stimulus funds. We will always monitor, always adjust, and always seek the right balance. Our progress depends on it.

Do we have enough resources? Of course not. We will never have enough money to do everything we want to do—or could do. Ours is not a bad system, but rather a responsible one. We strive to be good stewards of the people’s investment. From my desk, I am not seeing exciting, risky science going unsupported or witnessing stifled creativity in our programs. I see extremely dedicated scientists donating and sacrificing tremendous amounts of personal time to serve on review panels and to do their very best to make good judgments. They need to be given our loudest applause. That’s the story I wish I had read on Sunday.

In the end, it is about the power of research and the promise of hope.

Dr. John E. Niederhuber
Director, National Cancer Institute

Guest Commentary by Dr. Dr. Jeanette Vega

Chile and the United States—Forming a Proud Partnership

Dr. Jeanette VegaThat we live in a global community, one in which events in one city or country can have serious consequences for residents of another city or country thousands of miles away, is undeniable. Whether it’s the H1N1 virus pandemic, the current unrest in Iran, or the worldwide economic downturn, this interconnectivity obviously brings about significant challenges. But it can also create unprecedented opportunities, in particular those that may substantially improve public health.

An agreement announced last week between officials from the United States and the Republic of Chile provides a shining example of one such opportunity. Under a Letter of Intent (LOI) signed by NCI Director Dr. John E. Niederhuber and me, the partnership sets the stage for cooperative efforts between our countries in a number of important research areas, including basic and clinical cancer research, bioinformatics, and training and resource sharing.

NCI Director Dr. John E. Niederhuber and Chile's Undersecretary of Public Health Dr. Jeanette Vega signed a Letter of Intent on June 16.NCI Director Dr. John E. Niederhuber and Chile's Undersecretary of Public Health Dr. Jeanette Vega signed a Letter of Intent on June 16.

These efforts will be conducted under the auspices of the United States-Latin America Cancer Research Network, which was established this past March. Chile is a proud member of this network, along with Brazil, Argentina, Mexico, and Uruguay. The LOI between Chile and the United States is a direct outcome of this Network and reinforces what I believe are the keys to the success of such global initiatives: collaboration, collaboration, and collaboration.

The partnerships being created as a result of these activities set the stage for important progress throughout Latin America and the United States on cancer prevention, early detection, and treatment and survivorship, particularly with regard to cancers that have an outsized impact in Hispanic communities, such as breast cancer and, in Chile in particular, gallbladder cancer.

In fact, a research project on gallbladder cancer is one of three specific, high-priority activities that our two countries have chosen to pursue initially under this LOI. The other two are the creation of a national cancer registry and national tumor bank in Chile, both of which will enable Chilean scientists to conduct cutting-edge research and work more closely with their counterparts throughout the world.

Although gallbladder cancer is rare in the United States and many other countries, the incidence and mortality rates of this disease are particularly high among women in my country, and specifically among the Mapuche Indians, who primarily reside in central and southern Chile.

Working with NCI, we hope to conduct research that will help us better understand why gallbladder cancer rates are so much higher in certain Chilean populations, as well as to develop ways to reverse that trend. This is not a one-way street, however. Such efforts may well lead to a greater understanding of the natural history of gallbladder cancer, as well as greater insights into more effective modalities of its prevention, early diagnosis, and treatment, all of which are desperately needed, regardless of one’s country of residence.

During their meeting last week at the White House, U.S. President Barack Obama and Chilean President Michelle Bachelet both cited this new agreement between our countries as one of several important areas where we can jointly work to improve health and well being.

As the meeting of our countries’ respective leaders and the joint efforts that we are now undertaking demonstrate, we share the same important aims: to improve the lives of our citizenry through better medical care, educational and employment opportunities, and enhanced prosperity. By working together, I have no doubt we can achieve great ends.

Dr. Jeanette Vega
Undersecretary of Public Health, Republic of Chile

Special Report

MicroRNAs Show Promise for Detecting, Treating Cancer

Since James Watson and Francis Crick discovered the structure of DNA over 50 years ago, successive experiments by thousands of researchers worldwide have led to the central dogma of molecular biology: genes (DNA) encode RNA, which in turn directs the assembly of proteins. The hundreds of thousands of unique proteins produced by our genetic code in turn drive the workings of the body, including the regulation of which genes are expressed, when, and in what tissues.

Dr. Jonathan Mendell and colleagues used a virus encoded with a fluorescent green protein to deliver a microRNA to liver cells in mice. The mouse liver pictured here glows green, indicating that the microRNA successfully reached the liver. (Image courtesy of Drs. Janaiah Kota, Reed Clark, and Jerry Mendell of Nationwide Children's Hospital in Columbus, OH) Dr. Jonathan Mendell and colleagues used a virus encoded with a fluorescent green protein to deliver a microRNA to liver cells in mice. The mouse liver pictured here glows green, indicating that the microRNA successfully reached the liver. (Image courtesy of Drs. Janaiah Kota, Reed Clark, and Jerry Mendell of Nationwide Children's Hospital in Columbus, OH)

The relatively recent discovery of small functional RNAs, including a class of tiny RNAs barely more than 20 nucleotides in length called microRNAs, has upended the long-held belief that nucleotides are only passive carriers of genetic information. MicroRNAs, it turns out, are non-coding RNAs. They do not pass on the instructions for assembling proteins but, instead, act like proteins, serving as potent regulators of gene expression. MicroRNAs bind to messenger RNAs (mRNA), either blocking the translation of the mRNAs or targeting them for destruction by the cellular machinery.

MicroRNAs are now thought to regulate the expression of more than half of all mammalian genes, including those responsible for cellular processes such as cell growth (proliferation) and cell death (apoptosis). When these processes spiral out of control due to faulty regulation, the result can be cancer.

An Exploding Field in Cancer Research

“I think microRNAs are probably the most significant discovery in the last 10 years in molecular biology, in terms of understanding how the gene expression process and the cellular machinery are regulated,” said Dr. Daniel Gallahan, deputy director of NCI’s Division of Cancer Biology (DCB). “You’re now constantly seeing the discovery of new microRNAs associated with the cancer process.”

These discoveries began in 2002, when the laboratory of Dr. Carlo Croce, director of the Human Cancer Genetics Program at the Ohio State University, showed that two microRNAs are deleted or downregulated (their expression is decreased) in the majority of cases of chronic lymphocytic leukemia. This was the first discovery of aberrant microRNA expression in a human cancer, and it opened a floodgate of research in the field. To date, aberrant microRNA expression has been found in every tumor type tested and has also been implicated in cancer progression and metastasis.

Researchers are now studying how this knowledge can be applied in the cancer clinic. Because microRNAs are very specific for different types of tissues—the brain contains different microRNAs than the liver or the bladder—and even for types of cells within those tissues, researchers have been looking for diagnostic applications for the molecules. “I think there is no doubt that microRNAs will be exploited for diagnostic and prognostic purposes,” said Dr. Croce.

For example, in a recent study, microRNA signatures were able to distinguish the correct tissue for cancers of unknown primary origin with more than 90 percent accuracy. “This effort compares favorably with the best result so far using mRNA-expression levels and will probably continue to improve as larger sample sets are collected and profiled for expression of microRNAs,” concluded the authors, led by Drs. Nitzan Rosenfeld and Ranit Aharonov from Rosetta Genomics in Israel.

Therapeutic Promise

The role of microRNAs in carcinogenesis also makes them a promising target for treatment. Especially attractive is the fact that one microRNA can regulate many, even hundreds, of gene targets. Scientists have estimated that more than 1,000 individual microRNAs exist in humans, but very few of their targets have been identified to date.

“The field is grappling to understand whether these very potent phenotypes controlled by microRNAs are related to a few targets that are regulated very robustly, versus many targets that are regulated only subtly. There’s also a spectrum between those possibilities,” explained microRNA researcher Dr. Joshua Mendell, associate professor of Pediatrics and Molecular Biology and Genetics at Johns Hopkins University.

But if the microRNAs driving carcinogenesis can be identified, finding their targets may not be essential for exploring them therapeutically. In a proof-of-concept study in mice, Dr. Mendell and his colleagues recently showed that restoring the normal expression of a single microRNA in liver cancer cells was enough to induce tumor regression, even though the microRNA did not target the cancer gene that initiated the tumors. The technique used was completely nontoxic to normal liver cells, which already expressed the microRNA.

This concept holds promise for treating tumors driven by cancer genes that have proven extremely difficult to target, so called “undruggable targets” such as the gene KRAS. “In cancers in which we cannot target a specific gene, we might be able to take a shortcut and target the downstream microRNAs that are disregulated—basically target the consequence of that genetic mutation,” explained Dr. Croce.

Future Directions

In response to the exponential growth of research and interest in microRNAs, DCB recently held a 2-day MicroRNA in Cancer Biology think tank, bringing together scientists engaged in leading-edge research in the field of microRNA biology.

“We wanted to identify where the field was going and figure out if there was anything we can do to facilitate that work,” said Dr. Gallahan.

The participants identified many areas that could help rapidly advance microRNA research, including “better algorithms for predicting microRNA targets, systematic sequencing of known microRNAs, and transgenic mouse models, which could be used to understand the roles individual microRNAs play in cancer. And of course ways to fund and share these resources,” explained Dr. Chamelli Jhappan, program director in DCB’s Tumor Biology and Metastasis Branch, who organized the think tank.

The full report from the think tank will be available on the DCB Web site by the end of the year. Those who would like to be on a distribution list for the report may contact Dr. Jhappan at jhappanc@mail.nih.gov.

—Sharon Reynolds

Profiles in Cancer Research

Dr. Bryce Reeve

Dr. Bryce Reeve Psychometrician and Program Director, Outcomes Research Branch, NCI Division of Cancer Control and Population Sciences

Not everyone comes to cancer research via the usual path. Dr. Bryce Reeve is a native of Chapel Hill, NC, has a Ph.D. in psychometrics from “the University,” and insists with pride that he “bleeds Tar Heel blue.” When you hear that he was a math whiz in high school and see him now—revolutionizing the field of assessing quality of life and adverse events with an esoteric brand of modeling called item response theory—you may not think there are too many dots to connect. But you would be wrong.

His story emerged through the lens of an intensely personal experience. He expressed his frustration from a recent visit back to Chapel Hill, where the mother of a childhood friend is home after surgery for pancreatic cancer.

“Despite the medications and surgery, she’s still in excruciating pain,” said Dr. Reeve. “On one side of the scale is a mountain of scientific progress in cancer treatment. On the other is this wonderful woman, enduring nobly but ravaged by her cancer, without much hope. She’s not a complainer,” he explained, “but she still should be able to communicate her symptoms and experiences. I think we need to provide patients a voice, a language to express what they’re going through—an expectation that their experience is not just a disembodied ‘side effect’ to be listed on a chart while they face the often-grisly reality alone.”

That is precisely what his work at NCI is about.

When Dr. Reeve headed to engineering school at Virginia Tech in the late 1980s, he was fully prepared to work 60 hours a week to keep up with that regimented discipline. What he didn’t expect was that something as nonmathematical as his own quality of life might interfere. “It was all science and math, and I just wasn’t happy with my life,” he recalls. He dropped out, and for the next 5 years he paid his bills by taking reservations by phone for the airline industry.

Accurately capturing the symptoms and experiences of living with cancer requires effective communication between patients and their health providers Accurately capturing the symptoms and experiences of living with cancer requires effective communication between patients and their health providers

He eventually finished his undergraduate degree by taking night courses at the University of North Carolina at Chapel Hill (UNC). In the process he fell in love with psychology. Fascinated by what he was learning about the science of human personality and behavior, he found a way to combine it with math in a graduate program in psychometrics at his beloved UNC. His Ph.D. in 2000 coincided with NCI’s creation of an Outcomes Research Branch (the first at NIH), with Dr. Joseph Lipscomb as its first chief.

“When Joe interviewed me for this job, I told him that all I knew about cancer was that nobody wants it. Finding a mentor like him was the luckiest thing for me,” said Dr. Reeve. “The best minds in the field are now friends and colleagues. My learning curve looks like a rocket trajectory.” And the timing was right, but only when you count those 5 “lost years trying to find my way.”

“We were the lucky ones,” said Dr. Lipscomb, who is now Professor and Georgia Cancer Coalition Distinguished Cancer Scholar at the Emory University School of Public Health. “You just get an instinct about someone. Bryce was out on the leading edge of what we call the ‘modern’ school of measurement approaches. Even on our first phone conversation, he was obviously very bright and quick-witted, and we were hoping he could help us jump the cancer research measurement field into the future.”

Reporting the adverse events (AE) that cancer patients experience has become a critical aspect of clinical trials, but it wasn’t always so. Until the 1970s, AE reporting in retrospective studies was limited, often ignoring the severity and nuance of what patients were experiencing. As clinical trials began to assume a more central role, the process became more formalized with safety (toxicity) profiles, standardized terminology, and a grading system.

The current system in oncology, devised by NCI, is the Common Terminology Criteria for Adverse Events (CTCAE), used throughout the United States and beyond to report and grade both acute and late effects from therapeutic oncology interventions, including surgery, radiation, and chemotherapy.

“But we have a long way to go,” said Dr. Reeve. “It’s not only clinical trials, but patients everywhere in the health care delivery system. We make the physician the gatekeeper and rely on them to communicate with patients about any symptoms they may be experiencing. But it’s a huge burden for oncologists,” who are often focused on treatment.

“Finding better ways to capture what it’s really like to live with cancer, day-to-day, is what drives me,” he explained. And after a decade of such work, he is now recognized as one of the leading experts on an idea whose time has arrived: patient-reported outcomes (PRO). This approach incorporates the patient’s perspective more directly in assessing health-related quality of life (HRQOL), and can even help patients ascribe personal meaning to the burden of cancer.

PROs would prove to be the springboard, and Dr. Reeve’s contribution was to weave item response theory (IRT) modeling into the art of devising questionnaires that would more clearly capture a patient’s HRQOL. IRT is based on the idea that how a person will respond to a question depends on his or her personal experience of the HRQOL domain being measured by the questionnaire. For example, asking: “Do you feel exhausted?” is an indicator of fatigue reported by cancer patients. Those with severe fatigue are more likely to answer “Yes,” while those experiencing mild to moderate fatigue are more likely to answer “No.” The application of IRT models combined with qualitative methodologies enhances a questionnaire’s ability to capture a cancer patient’s experience with minimal response burden. “Throughout the past decade, IRT methods have increasingly been used to great effect in PRO assessment,” said Dr. Reeve.

“Of course a patient’s disease status matters,” he explained, “but cancer is a journey. Every patient comes to see things differently, re-evaluate which daily activities mean the most, and ultimately to find a new set of priorities, if not values. We can’t overlook the human cancer patient in our crusade to cure the disease. With these new ways of specifying—and honoring—their experience, I think we’re on the right track. It’s really a privilege to do this work.”

In 2006, Dr. Reeve organized a major conference at NCI that produced a consensus: For subjective symptoms, the patient’s own account should be considered the gold standard. Entire domains of oncology, such as survivorship, palliative care, and quality of care, are being reinvigorated with just such a patient-centric emphasis. “We’re really beginning to redefine the basic model of care,” Dr. Reeve said.

Addison Greenwood

Featured Clinical Trial

Testing Trabectedin in Pediatric Patients

Name of the Trial
Phase I Study of Trabectedin in Pediatric Patients with Relapsed or Refractory Solid Tumors (NCI-07-C-0054). See the protocol summary.

Principal Investigators
Dr. Elizabeth Fox and Dr. Meredith Chuk (Lead Associate Investigator), NCI Center for Cancer Research

Why This Trial Is Important
New chemotherapy treatments for childhood cancers are often based on drugs developed to treat adult cancers. However, adults and children may not always react the same way to the same drugs. Because children’s bodies are undergoing rapid growth and development, pediatric patients may be adversely affected in ways not seen in adult patients. That is why researchers believe it is critically important to conduct early phase clinical trials to find the best dose of a new drug for children with cancer and to determine any side effects in these young patients.

Trabectedin was originally derived from the Mangrove tunicate, a species of sea squirt. (Photo courtesy of Kathy Hill, Smithsonian Marine Station at Fort Pierce) Trabectedin was originally derived from the Mangrove tunicate, a species of sea squirt. (Photo courtesy of Kathy Hill, Smithsonian Marine Station at Fort Pierce)

A new drug called trabectedin (Yondelis, ET-743), which was originally obtained from marine creatures known as sea squirts, is being developed for the treatment of adult patients with soft tissue sarcoma, ovarian cancer, and other solid tumors. This drug is now made in the laboratory and appears to kill cells by damaging their DNA and by interfering with DNA repair. In laboratory and animal testing, trabectedin was shown to be effective in killing cancer cells from several different types of solid tumors that occur in children, leading researchers to pursue its development for use against these pediatric cancers.

In this trial, children with solid tumors that have either recurred or have not responded to previous treatment will be treated with trabectedin. The patients will receive trabectedin by intravenous infusion over a 24-hour period once every 21 days. The doses will be increased in consecutive groups of patients until the maximum tolerated dose is reached. The side effects of trabectedin will also be determined.

“Although this drug has undergone limited testing in pediatric patients using a shorter infusion schedule, we need to establish the maximum tolerated dose with this new 24-hour infusion schedule, which is the recommended schedule for adults,” said Dr. Fox. “In addition, most research on trabectedin use in children focuses primarily on patients with sarcoma. We hope to also recruit patients with non-sarcoma cancers, so we can explore the drug’s potential in a broader range of childhood cancers.”

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

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

Notes

Dr. Diane Meier Participates in White House Health Reform Stakeholder Discussion

Dr. Diane Meier Dr. Diane Meier

On June 18, Center to Advance Palliative Care (CAPC) Director and NCI-grantee Dr. Diane Meier joined the third and last White House health care stakeholder discussion on health reform. The discussion was held by Nancy-Ann DeParle, director of the White House Office of Health Reform, and it focused on prevention and cutting the cost of care.

Dr. Meier and Ms. DeParle were joined by Dr. Ezekiel Emanuel from the Office of Management and Budget, Dr. Bob Kocher from the National Economic Council, Dr. Kavita Patel from the Office of Public Engagement, and Dr. Dora Hughes from the Department of Health and Human Services, who co-moderated the discussion.

Prior to the discussion, Dr. Meier said, “I am thrilled to have this opportunity to speak directly with the White House about the important role palliative care can play in providing high quality, yet very cost-effective care for patients facing serious and chronic illness.” At the meeting, she told the panel that preventing the wrong care can help save the health system money that can be used to pay for wellness and prevention. “Americans are aging with serious, chronic illnesses, but despite enormous expenditures, they still get uncoordinated care, extreme burdens on their families, and poorly managed pain.”

NCI Scientists Featured in Journal of Minority Medical Students

A Journey of Discovery

The careers and contributions of several NCI scientists were recently profiled in a special supplement to the Journal of Minority Medical Students. The supplement, A Journey of Discovery, highlights NCI training programs and is intended to motivate up-and-coming minority biomedical scientists to chart their own cancer research careers.

Some of the featured researchers include Dr. Sam Mbulaiteye of NCI’s Division of Cancer Epidemiology and Genetics, Dr. Worta McCaskill-Stevens of NCI’s Division of Cancer Prevention, Dr. Jeffrey White, director of NCI’s Office of Cancer Complementary and Alternative Medicine, and Dr. Lauren Wood of NCI’s Center for Cancer Research.

Drs. Mbulaiteye, Wood, and White were joined by Dr. Maria Cantu of NCI’s Center to Reduce Cancer Health Disparities in April for a national radio tour to promote cancer research careers for National Minority Cancer Awareness Week. The radio tour was organized by the NCI Office of Communications and Education’s Multicultural Media Outreach team.

These researcher profiles were adapted for the NCI training portal on Cancer.gov. The portal contains links to profiles and interviews of minority cancer researchers and students at different stages of their education and careers.

caBIG Annual Meeting Slated for July

Logo for the caBIG 2009 Annual Meeting

The 2009 cancer Biomedical Informatics Grid (caBIG) annual meeting will take place at the Marriott Wardman Park Hotel in Washington, DC, on July 20–22.

caBIG has been developed to enable the sharing of data and knowledge, simplify collaboration, speed research delivering diagnostics and therapeutics to the clinic, and realize the potential of personalized medicine. It connects major segments of the cancer community—linking the NCI-designated Cancer Centers, Community Cancer Centers, large-scale NCI science endeavors, and countless scientists. caBIG capabilities also provide a platform for other disease communities.

Admission is free and open to the public. Registration, however, is required. More information and registration are available online.

BSA Meeting Held

NCI's Board of Scientific Advisors (BSA) met June 22 on the NIH campus in Bethesda, MD. The public portions of the meeting can be viewed online.