National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 2, 2010 • Volume 7 / Number 21

BREAKING NEWS

Lung Cancer Trial Results Show Mortality Benefit with Low-Dose CT

(UPDATE – November 4, 2010) NCI has released initial results from the National Lung Screening Trial (NLST), a randomized national trial involving more than 53,000 current and former heavy smokers ages 55 to 74. The trial compared the effects of two lung cancer screening procedures—low-dose helical computed tomography (CT) and standard chest X-ray—on lung cancer mortality and found 20 percent fewer lung cancer deaths among trial participants screened with low-dose helical CT. Read more >>

NEWS

CT scans showing a liver IMT before and after 13 weeks of crizotinib treatment (Image courtesy of the New England Journal of Medicine. 2010 Oct 28;363(18):1760-2)Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

New data from a phase I trial of crizotinib, a small-molecule drug that targets cancer-causing chromosomal rearrangements involving the gene ALK, in patients with non-small cell lung cancer (NSCLC) add to positive results presented earlier this year at the American Society of Clinical Oncology annual meeting. Read more > >

A MESSAGE TO READERS

Communications SeriesOncology Nursing Series
Survivorship Series Technology Series

Series Archives Now Available

Last year, the NCI Cancer Bulletin began publishing four new series of articles that focus on the topics of Survivorship, Technology, Communications, and Oncology Nursing. Each series featured an icon that identified the topic. Readers can access a full list of the articles in each series by clicking on the icon. Look for additional articles on these and other topics in the future.

  

IN DEPTH

UPDATES

  • FDA Update

    • Labeling Change Includes Warning for a Class of Prostate Cancer Drugs
    • Dasatinib Approved as First-line Treatment for Chronic Myelogenous Leukemia
    • Trastuzumab Becomes First Targeted Therapy Approved for Stomach Cancer
  • Notes

    • In Memoriam: Joan Mauer, Chief of NCI’s Clinical Trials Monitoring Branch
    • NCI to Co-host Scientific Journalism Workshop in Rio de Janeiro

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.

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

Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

CT scans showing a liver IMT before and after 13 weeks of crizotinib treatment (Image courtesy of the New England Journal of Medicine. 2010 Oct 28;363(18):1760-2) In a patient with an inflammatory myofibroblastic tumor (IMT) that had an ALK gene rearrangement, the drug crizotinib caused tumor shrinkage and disease stabilization. These CT scans above show a liver IMT before (left, circled in red) and after 13 weeks of crizotinib treatment (right). (Image courtesy of the New England Journal of Medicine. 2010 Oct 28; 363(18): 1760-2) Click to Enlarge.

New data from a phase I trial of crizotinib, a small-molecule drug that targets cancer-causing chromosomal rearrangements involving the gene ALK, in patients with non-small cell lung cancer (NSCLC) add to positive results presented earlier this year at the American Society of Clinical Oncology annual meeting. Researchers led by Dr. Eunice Kwak of Harvard Medical School reported that more than half of patients who have an ALK rearrangement and who received crizotinib had partial or complete shrinkage of their tumors. The updated results were published October 28 in the New England Journal of Medicine (NEJM).

In comparison, only about 10 percent of lung cancer patients who receive second-line chemotherapy respond to treatment. “It is gratifying to learn of responses like those seen in our study…especially when you consider that most patients had already received two or more therapies by the time they entered the trial,” stated Dr. Kwak in a press release.

The trial, which was sponsored by the drug’s developer, Pfizer, Inc., began as a dose-escalation study in patients with many different solid tumors to determine the maximum safe dose of crizotinib. Later, only patients with solid tumors that had proven molecular abnormalities thought to be targeted by crizotinib, including ALK gene rearrangements in lung cancer, were eligible to enroll.

The NEJM paper reported that 46 of the 82 NSCLC patients had a partial response (their tumors shrank by at least 30 percent in diameter) and one had a complete response. An additional 27 patients had stable disease (i.e., their tumors stopped growing during treatment). The researchers estimated the probability of being alive without progression of disease after 6 months of treatment to be 72 percent. Crizotinib led to few major side effects, and the most common low-grade effects included nausea, diarrhea, and mild visual disturbances.

Additional data from an expanded cohort of 113 patients were presented October 10 at the 2010 European Society for Medical Oncology (ESMO) Congress. Those data showed that response rates remained high, at 56 percent (including partial and complete responses), and that median progression-free survival was 9.2 months.

“As we added more patients to the study, the results remained entirely consistent, and the benefit is consistent across the line of therapy, sex, age, and general fitness,” said Dr. Ross Camidge from the University of Colorado Cancer Center, an investigator on the trial who presented the data at the ESMO meeting. “That’s consistent with an agent that’s actually addressing the root cause of the cancer.”

Although only 2 to 7 percent of all NSCLC patients have tumors with the ALK genetic change, the sheer number of lung cancer cases diagnosed each year means that “the number of potential patients for crizotinib therapy is substantial, approaching 10,000 annually in the United States alone,” wrote Drs. Bengt Hallberg and Ruth Palmer from Umeå University in Sweden, in an accompanying editorial in NEJM. A phase III trial comparing crizotinib with standard chemotherapy in patients with advanced NSCLC that harbors an ALK gene rearrangement is ongoing.

Two additional articles in the October 28 NEJM about specific patients in the phase I trial shed some light on the potential future of crizotinib—both the good and the bad. In a case report published by researchers from Dana-Farber Cancer Institute and their colleagues, crizotinib caused disease regression in a patient with inflammatory myofibroblastic tumor (IMT), a rare type of sarcoma in which ALK gene rearrangements are common. In a second case report, researchers at Jichi Medical University in Japan analyzed how new mutations in the ALK gene of another patient led to emerging resistance of his lung tumor to crizotinib.

The case report from Dana-Farber took a closer look at two patients with IMT who had been enrolled in the original dose-escalation portion of the trial. Although both patients had IMT, only one patient turned out to have an ALK-positive cancer. That patient remained alive and in remission and was still receiving the drug at the time of publication, whereas the ALK-negative patient’s disease progressed almost immediately despite crizotinib treatment.

“Given these positive and negative examples and the rarity of the diagnosis, one can extrapolate that ALK inhibitors are appropriate therapy for people with ALK translocation-positive inflammatory myofibroblastic tumor,” said Dr. Robert Maki, a medical oncologist at Memorial Sloan-Kettering Cancer Center and an author on the paper. Recurrent IMTs are often resistant to traditional chemotherapy drugs.

“There’s increasing interest in targeted drugs for rarer cancers—researchers are branching out more and more,” explained Dr. Maki. “This is one of several recent examples of the personalization of medicine based on the targets that are known to be important in a given person’s tumors.”

Unfortunately, a persistent frustration found in the development of targeted drugs is that most tumors eventually develop mutations that confer resistance to the treatment. In the case report from Japan, researchers studied a patient from the phase I trial who developed resistance to crizotinib after 5 months of treatment.

The researchers identified and sequenced two independent mutations in the patient’s rearranged ALK gene that could block the response to crizotinib. These mutations likely alter the structure of the ALK protein, thereby preventing the drug from binding to the protein and diminishing its activity, explained the authors.

It is unknown how common these specific mutations will be in a larger group of patients, said Dr. Camidge, although it is likely that, through a variety of mechanisms, every patient will eventually develop resistance to the drug, he explained. “Every patient that progresses either has primary resistance—that’s the 10 percent or so of patients who don’t respond at all—or initially responds but then acquires resistance.”

One solution to this problem, said Dr. Maki, will be the development of drugs that can bind to mutated ALK proteins, much as dasatinib binds the BCR-ABL protein in patients with chronic myelogenous leukemia (CML). Dasatinib is used to treat imatinib-resistant CML by more broadly blocking the kinase that drives CML, he explained.

Widespread use of drugs tailored to the mutations that drive individual tumors will require the genotyping of tumors, and methods like those currently being employed at Dana-Farber Cancer Institute, the University of Colorado, and other centers are the first step toward making tumor genotyping a standard part of cancer diagnosis. “That’s going to become part of the routine work-up of cancer [patients],” Dr. Maki said. “The genetic changes found in a tumor are eventually going to be more important than whether the cancer began in the colon or the pancreas or the breast.”

—Sharon Reynolds

Cancer Research Highlights

Pancreatic Cancers May Develop Slowly Over Many Years

Pancreatic cancers may take more than a decade to progress to a lethal stage, according to an analysis of genetic changes in tumors from seven patients. The findings, which appeared October 28 in Nature, surprised even the researchers themselves by indicating that there is a long lag time between the first cancer-causing genetic change in a pancreatic lesion and the development of life-threatening metastatic disease. This lag time represents a window of opportunity for detecting the cancer in its early stages, the researchers noted.

The study, by researchers at Johns Hopkins’ Sol Goldman Pancreatic Cancer Research Center, contradicts a widely held view that the disease is so deadly because it spreads rapidly. Pancreatic cancer is frequently diagnosed only after the disease has spread to other tissues, and many patients do not survive beyond a year.

The research builds on a genomic analysis of 24 pancreatic cancer genomes that was reported in 2008 by the Hopkins researchers. In the current study, the researchers carried out a genetic analysis of multiple different regions within a single patient’s primary pancreatic tumor. After identifying cancer-related mutations in regions of the primary tumor and in metastatic tumors of seven of the original patients, the researchers used mathematical models to estimate the timeline of pancreatic cancer progression. 

On average, the researchers estimated, 11.7 years had passed between the initiating mutation in the tumor cell and the development of the first cancer cell that gave rise to the “parental clone,” which contains all of the mutations known to drive pancreatic cancer development. Another 6.8 years passed before at least one subclone had gained the genetic potential to spread. From that point, another 2.7 years, on average, passed before the patients’ deaths.

“We were all surprised by how slow the natural history of pancreatic cancer seems to be,” said lead researcher Dr. Christine Iacobuzio-Donahue. “This disease seems to be so lethal, and the feeling among many people has been that you can’t do anything about pancreatic cancer. But we now know that it takes years for metastases to develop. So we finally have an idea of what we need to do in terms of early detection and when we need to do it.”

In an accompanying study published in Nature, researchers at the Wellcome Trust Sanger Institute profiled genomic rearrangements—chromosomal alterations that result when DNA has been broken and shuffled in some way—in primary and metastatic pancreatic tumors from 13 patients. Most of the rearrangements were found to occur early in the disease. The ability “to identify and understand these early mutations provides a route to the discovery of drug targets,” the study authors concluded. 

Cetuximab May Benefit Some Patients with KRAS Gene Mutations

European researchers have found evidence that colorectal cancer patients with a specific mutation in the KRAS gene may benefit from the targeted drug cetuximab. Previous studies had indicated that patients with mutant KRAS derive no benefit from cetuximab, and the American Society of Clinical Oncology has recommended that patients with mutated forms of KRAS not receive the drug. This new retrospective analysis of data from 579 patients with chemotherapy-resistant colorectal cancer was published October 27 in JAMA.

Researchers led by Dr. Wendy De Roock from the University of Leuven in Belgium analyzed data from patients with advanced colorectal cancer who had received cetuximab, with or without chemotherapy, in six clinical trials or who had received cetuximab outside of a clinical trial. They compared survival of patients with the normal KRAS gene, patients with the most common mutation in a part of the KRAS gene called codon 13, and patients with all other KRAS mutations.

Patients with the mutation in codon 13 (called p.G13D) survived for longer than patients with other KRAS mutations who received cetuximab (medians of 7.6 months versus 5.7 months). In addition, overall survival was similar between patients with the p.G13D mutation and patients with a normal KRAS gene.

In a corresponding set of experiments in cell lines, the researchers found that cetuximab inhibited the growth of colorectal cells containing the normal KRAS gene and cells containing the p.G13D mutation, but not cells with other KRAS mutations. The researchers observed the same pattern when cetuximab was given to mice implanted with colorectal cancer cells.

Because the new analysis of patient data “is a retrospective observational study that relies largely on nonrandomized or cross-trial comparisons…it can therefore only suggest an association between p.G13D mutation status and survival benefit after cetuximab-based treatment,” stated the authors. They concluded that prospective randomized trials in patients with the p.G13D mutation are needed “before conclusions about potential beneficial effects of cetuximab…should be inferred.”

Protein Found on Tumor Blood Vessels Might Be Cancer Target

A cell-surface protein called the follicle-stimulating hormone (FSH) receptor, which was previously thought to exist only in specialized areas of the ovaries and testes, has been found on the surface of blood vessels in 11 different tumor types but not in the surrounding normal tissue. The results of the study, published October 21 in the New England Journal of Medicine, raise the possibility that the receptor could potentially be exploited for cancer imaging and targeted treatments.

Researchers led by Dr. Aurelian Radu from Mount Sinai School of Medicine examined tumor samples taken from 1,336 cancer patients who had not received chemotherapy or hormone therapy before surgery. Blood vessels that had the FSH receptor were found at the periphery of every tumor sample taken from 773 men with prostate cancer.

In a follow-up set of samples from 563 patients with 10 different tumor types, the FSH receptor was also found in each sample, regardless of tumor type or stage. The researchers also examined normal tissue samples and noncancerous tissue samples taken from inflammatory, regenerative, or proliferative diseases or conditions, and did not find FSH receptors.

With the exception of those in the kidney cancer samples, the blood vessels that had FSH receptors were restricted to the periphery of the tumors, in a layer approximately 10 mm thick. An imaging agent that could specifically target the FSH receptor could be used to define the boundary between normal and tumor tissue for surgery or radiation therapy, the authors hypothesized.

In an in situ test, the researchers perfused euthanized mice carrying prostate tumor xenografts with a solution of antibodies that attach to the FSH receptor, bound to a molecular imaging agent. The antibodies selectively bound to the outside of tumor blood vessels, and the imaging agent was taken up by the blood vessel cells. However, the researchers cautioned that because of the way the experiments were carried out, their results “cannot be considered to be a proof-of-principle demonstration that the FSH receptor expressed on tumor-associated blood vessels can be exploited clinically.” But since the FSH receptor may play an important biological role in tumor blood vessel formation, they hypothesized that blocking FSH-receptor signaling could be a new strategy against tumors.

More Evidence Suggests Aspirin May Prevent Colorectal Cancer

While previous results have shown that aspirin and celecoxib (a selective COX-2 inhibitor) reduce the risk of colorectal adenomas and precancerous polyps in people at high risk, a new meta-analysis showed that both colorectal cancer and deaths from the disease may be reduced by long-term daily use of aspirin. The results were published online October 21 in The Lancet.

Dr. Peter Rothwell of the University of Oxford and his colleagues calculated 20-year risk estimates by pooling data from more than 14,000 patients enrolled in five randomized trials conducted in the United Kingdom, Sweden, and the Netherlands. The trials were designed to study the effect of aspirin on the risk of heart attack and stroke, but cancer data were collected as well. The researchers found that patients who took at least 75 mg of aspirin daily for about 5 years had a 24 percent lower risk of colorectal cancer and a 35 percent lower risk of dying from the disease.

For those trials where data were available for sites within the colon, the preventive benefit of aspirin appeared to be confined primarily to the proximal colon, with a reduction in incidence of about 55 percent. Cancer incidence in the distal colon was not reduced. This distinction is important because colorectal cancer screening with sigmoidoscopy, the screening approach more commonly used in Europe, does not detect cancer in the proximal colon. (Although colonoscopy, the approach more commonly used in the United States, surveys the entire colon, its benefits may be limited mainly to the more distal part of the colon.)

The authors acknowledged a number of limitations to the study. They noted, for example, that they “did not model the effect of the reduction in deaths due to colorectal cancer on the overall balance of risk and benefit of long-term use of aspirin,” which can cause nausea, heartburn, and irritation and bleeding in the intestines, bowel, and stomach. In addition, they noted, the five trials included in the study “predated endoscopic screening for adenomas, which also reduces colorectal cancer incidence and mortality, and might therefore reduce the absolute benefit of aspirin.”

“These findings represent some of the longest follow-up data following 5 years of treatment,” said Dr. Ernest Hawk of the University of Texas M. D. Anderson Cancer Center. “They also answer a long-standing question: what dose is required for a protective benefit? This study suggests that 75 mg is adequate.”

Also in the News: Experimental DNA Test May Detect Colorectal Polyps and Cancer

An investigational screening test for colorectal cancer that detects DNA mutations or methylations in stool samples shows promise in detecting both precancerous adenomas and cancers, researchers from the Mayo Clinic and Exact Sciences reported last week. The findings, from the first clinical validation study of the next-generation test, were presented at the American Association for Cancer Research special conference, Colorectal Cancer: Biology to Therapy, in Philadelphia.

The test, which detects genetic changes known as methylation to several genes and mutations in the KRAS gene, identified nearly 64 percent of adenomas greater than 1 cm in size and 85 percent of cancers, based on known findings in the patients from whom the samples were taken. The test picked up adenomas and cancers regardless of their location in the colon, explained lead investigator Dr. David Ahlquist of the Mayo Clinic. The detection figures were based on a test designed to have 90 percent specificity, meaning it would be expected to have a false-positive rate of 10 percent, Dr. Ahlquist said.

The researchers used stored stool samples from patients from four different centers, but there was no standardized system for sample collection or storage, Dr. Ahlquist noted. Prospective studies of the test are expected to begin next year. Mayo stands to receive royalty and other payments from Exact Sciences under a licensing agreement with the company, Dr. Ahlquist said.

A Closer Look

Engineering Progress against a Rare Cancer

An MRI scan of a 17-year-old male showing a chordoma extending from the nasal cavity to the brainstem. (Image courtesy of S Hassan, JM Abdullah, SJ Wan Din, and Z Idris) An MRI scan of a 17-year-old male showing a chordoma extending from the nasal cavity to the brainstem. (Image courtesy of S Hassan, JM Abdullah, SJ Wan Din, and Z Idris)

In 2006, during his freshman year at Duke University, Josh Sommer learned that the persistent headaches he was experiencing were caused by a tumor pressing on his brain stem. When surgeons removed the tumor, tests showed that it was a rare bone cancer known as chordoma. Just days after the procedure, Sommer began to download and read on his laptop computer every chordoma study he could access through the Duke library.

Unfortunately, he learned that patients with the disease live, on average, only 7 years after diagnosis. Chordomas can occur anywhere along the spinal column, from the base of the skull to the tailbone. Most chordomas grow slowly, but they are usually fatal. The 300 or so people who are diagnosed with the disease in the United States each year have few treatment options beyond surgery and radiation.

When Sommer returned to school in the fall, he was determined to help find a cure for his disease. In addition to his engineering classes, he joined the lab of Dr. Michael Kelley, a cancer researcher who, along with colleagues at NCI, had begun to look for chordoma genes in high-risk families. Sommer joined the ongoing effort to identify genetic regions of interest by profiling the activity of a gene that experts suspected might play a role in chordoma. The gene is called T, or Brachyury (for the protein it encodes—a transcription factor that regulates the activity of other genes).

But the evidence tying the gene to the disease was preliminary, and Sommer began to wonder whether his research would make a difference. “I remember riding my bike to the lab—sometimes in the rain—and thinking, is this really how I should be spending my time?” he recalled recently.

Four years later, his doubts are gone. There is growing evidence that the Brachyury/T gene may play a role not only in chordoma but also in other cancers as well. Sommer, now 22 years old and on leave from Duke, has dedicated himself to improving the lives of patients with chordoma. He recently became executive director of the Chordoma Foundation, an organization he co-founded in 2007 with his mother, Dr. Simone Sommer, to accelerate research on the disease.

A Duplicated Gene

Researchers know that chordomas arise from remnants of the notochord, which is an embryonic precursor to the spinal cord. The Brachyury/T gene regulates the development of the notochord in embryonic cells and is expressed in virtually all chordomas but not in most normal adult tissues.

The abnormal expression of the Brachyury/T gene in chordoma appears to be associated with the presence of extra copies of the gene. The most recent evidence comes from a report published last month showing that extra copies of the gene are common in chordoma tissue from patients with noninherited, or sporadic, forms of the disease.

This finding, by Dr. Adrienne Flanagan of University College London and her colleagues, is consistent with a study published last year that found extra copies of the gene in the germline DNA of patients with the familial or inherited form of the disease.

“Together, these results support a major role for changes to the Brachyury/T gene in the development of chordoma,” said Dr. Rose Yang of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Dr. Yang was first author of the familial chordoma study, a long-term study of high-risk families co-led by Dr. Dilys Parry of DCEG and carried out in collaboration with Dr. Kelley’s lab at Duke.

Dr. Yang pointed out another similarity between the studies: each found higher levels of the brachyury protein even in some patients who did not have extra copies of the gene itself. “This highlights the need to identify mutations in other genes or an as-yet-unknown mechanism for improperly activating the production of brachyury in both familial and sporadic chordoma,” she noted.

Josh Sommer working in Dr. Michael Kelley’s laboratory at Duke University Josh Sommer working in Dr. Michael Kelley’s laboratory at Duke University

Exploring a Cancer Vaccine

Brachyury is also the focus of an effort under way at NCI to develop a cancer vaccine for patients with common cancers such as lung, breast, and colorectal. The Brachyury/T gene may be improperly switched on in these cancers, and cells expressing this protein could potentially be recognized and targeted by human immune cells, Dr. Claudia Palena of NCI’s Center for Cancer Research (CCR) and her colleagues said in a study published a few years ago.

More recently, the researchers reported that the Brachyury/T gene may promote a process known as the epithelial-mesenchymal transition in cancer cells, which makes them more invasive and better able to spread. The idea behind the vaccine would be “to stop this process in its tracks,” said Dr. Jeffrey Schlom of CCR’s Laboratory of Tumor Immunology and Biology, who is leading the project.

A phase I clinical trial to establish the safety and proper dose of the experimental vaccine could begin within a year. Although preliminary, “the work represents a nice example of developing a potential treatment for common cancers that could be applicable to rare cancers,” said Dr. Schlom.

In the Kelley lab at Duke, the work on the Brachyury/T gene started when Sommer undertook a project to characterize tumor cell lines that were said to be derived from chordoma. But the researchers soon learned that several cell lines published as being chordoma clearly were not. (A manuscript with the results is under review.) 

“The positive outcome of this work, which Josh was instrumental in advancing, is that there are now two cell lines that are well characterized as being derived from chordomas and may be useful models,” said Dr. Kelley. “The work on Brachyury began as part of his work on those cell lines and has now broadened significantly, both in our lab and others.”

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Overcoming Barriers to Research

During his time in the lab, Sommer saw firsthand the challenges of trying to study a rare disease. Critical resources, such as cell lines, tissue samples, and animal models, were scarce or did not exist. Nor was it clear who else was studying chordoma and, therefore, could be potential collaborators. “After some initial progress, we were hitting a wall,” Sommer recalled.

The Chordoma Foundation aims to overcome those barriers by building networks of researchers, funding the development of research tools and treatments, and creating ways for researchers to share their results as soon as possible. The hope is that potentially life-saving results could be shared almost in real time, rather than waiting months or years for publication in a medical journal, as often happens now.

“The biggest challenge with chordoma is the rarity of the disease,” said Dr. Paul Meltzer of CCR and a member of the Chordoma Foundation’s board of scientific advisers. “I work on a lot of uncommon cancers, and this is one of the rarest. It’s hard to study something when you can’t get tissue samples or reagents. You also need to get cooperation among the centers that see patients so that researchers can talk and share results.” Dr. Meltzer has seen patient-driven advocacy organizations for less-common cancers “spring up from time to time,” and the Chordoma Foundation is one of the most effective efforts he’s seen.

“Josh is an incredibly talented young man who has used his abilities to push for research on chordoma and hopefully new therapies,” said Dr. Meltzer. “He brought the disease to the attention of people at the highest levels of cancer research who wouldn’t have heard of it otherwise. He has a real chance of helping the chordoma field and patients with this disease.”

Bringing Researchers Together

Over the past 3 years, the Chordoma Foundation has brought together more than 100 investigators for two international scientific conferences. The Foundation has also funded research in seven labs and developed a research roadmap that “will ultimately lead us to the point of having a really good shot at curing this disease,” said Sommer. 

The Chordoma Foundation has helped the field in a number of ways, said Dr. Kelley. “The foundation was instrumental in stimulating more interaction among investigators who had not previously been communicating with one another. This led to new collaborations and the sharing of data.” The foundation also provides useful information about the disease and treatment options for patients and families, he added.

Among the researchers supported by the foundation is Dr. Vijaya Ramesh of Massachusetts General Hospital, whose lab studied several rare cancers, but not chordoma. After she published findings related to chordoma, however, Dr. Simone Sommer contacted her, and she is now collaborating on a project to develop a mouse model for the disease.

“The foundation pushed us researchers to all think about the disease together, and I’m happy to have been involved,” said Dr. Ramesh. But she was also realistic about the future: “Whether we can move this research forward really depends on what we learn from the mouse models and whether there is additional funding.”

Josh Sommer has been free of tumors for 4 years, and he goes back to the hospital for scans every 6 months. “For the most part, I’m able to put my disease out of my head and really focus on the job at hand,” he said. “But it hits home when I hear from patients who are struggling with the disease or about patients having a recurrence who are just being ravaged by this disease.

“Their stories are constant motivation to work as hard as possible and do everything we can to bring researchers together and to raise the funds to make the research happen,” he added.

—Edward R. Winstead and Sarah Curry

See also: Duplicated Gene May Explain Rare Cancer in Some Families

Featured Clinical Trial

Targeted Antibody Therapy for Metastatic Adrenocortical Carcinoma

Name of the Trial
Phase II Randomized Study of Mitotane with Versus without Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12 in Patients with Recurrent, Metastatic, or Primary Unresectable Adrenocortical Carcinoma (UCCRC-16402A). See the protocol summary.

Dr. Gary Hammer Dr. Gary Hammer

Principal Investigator
Dr. Gary Hammer, University of Michigan Comprehensive Cancer Center

Why This Trial Is Important
Adrenocortical carcinoma (ACC) is a rare type of cancer that forms in the outer layer, or cortex, of the adrenal gland. The only potential cure for this disease is surgical removal (resection) of the affected gland. However, many patients are not diagnosed until the disease has become widespread (metastasized).  Moreover, the recurrence rate among patients treated with surgery is high. Patients with advanced or recurrent ACC are often treated with the drug mitotane (Lysodren), which is the only drug currently approved by the FDA to treat the disease. Unfortunately, many patients do not respond to the drug or become resistant to treatment with it. Therefore, doctors are eager to find more effective treatments.

The insulin-like growth factor (IGF) signaling pathway is thought to be important in the development and growth of ACC. The IGF pathway is activated by interactions between the circulating growth factors IGF-1 and IGF-2 and their membrane-bound receptor, IGF-1R. A number of agents are being developed that target this pathway by blocking the ability of IGF-1 and IGF-2 to bind to and activate IGF-1R. One such agent is a monoclonal antibody called IMC-A12 (cixutumumab). Doctors want to know if combining IMC-A12 with mitotane will help stop the growth of recurrent, metastatic, or unresectable ACC. In preclinical studies, this combination was more effective than mitotane alone at inhibiting growth of ACC tumors in animal models. In a phase I clinical trial, patients with metastatic ACC that was unresponsive to other therapies were treated with a different monoclonal antibody that targets IGF-1R; although none of the patients had an objective response, the majority experienced stable disease and minor tumor shrinkage. 

In this clinical trial, 20 patients with recurrent, metastatic, or otherwise unresectable ACC who have not been previously treated with systemic therapies will be treated with IMC-A12 and mitotane to determine the safety of the combined therapy. If the combination is safe, an additional 102 patients will be randomly assigned to receive the combined treatment or mitotane alone. Doctors want to see if the combination therapy will improve progression-free survival compared with mitotane alone. They will also try to determine whether either treatment improves quality of life or response rates

“Research by many investigators including those at the University of Michigan has focused on trying to understand the role of IGF in adrenal cancer, particularly the role of IGF-2, the levels of which can be elevated 90- to 100-fold in some cases,” said Dr. Hammer. “What this research suggests is that, if elevated levels of IGF-2 are part of the etiology of the disease, then that may be a very targetable defect.

“The antibody being tested in this trial has a mechanism of action that involves not just blocking the ability of IGF-2 to bind to IGF-1R, but also causing internalization and degradation of the receptor. So the receptor is simply not there for the growth factor to attach to and stimulate growth of the cancer cell,” he added.

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

Community Update

Recognition of Animal Welfare in Biomedical Science Takes Center Stage

Office of Laboratory Animal Welfare logo

A quarter of a century ago, a landmark NIH symposium, “Animal Welfare and Scientific Research,” fostered new laws and policies safeguarding the welfare of animals used in biomedical research. Last week, federal research leaders, scientists, animal rights activists, and others gathered again for a conference near the NIH campus to acknowledge the critical contributions research animals have made to accelerating biomedical discovery over the last 25 years and to improving human and animal health.

The original NIH symposium, held in April 1984, led directly to new federal policies for the use and care of vertebrate animals in testing, research, and training. The event also contributed to the passage of laws that mandated humane care of laboratory animals, including requirements for Institutional Animal Care and Use Committees (IACUC) to provide local oversight for U.S. Public Health Service-supported research that involves animals.

NIH Deputy Director for Extramural Research Dr. Sally Rockey noted that about 40 percent of NIH-funded grants and contracts currently involve animal research. In 2009, she said, the intramural laboratories at NIH used over 1.3 million animals, representing more than 20 species, for research studies.  (Mice are used in 81 percent of NIH intramural animal studies.)

Through its Office of Laboratory Animal Welfare (OLAW), NIH requires all grantee institutions to maintain IACUCs and provide training on the humane practice of animal care for people who are involved in animal research projects. Individual research grant applications must also state why animals are needed for the funded research.

“The astonishing conservation of gene function across vast evolutionary distance has made animal models more useful than we could have imagined and probably accelerated biomedical research by decades, if not centuries,” said Dr. Nancy Hopkins, a professor of biology at the Massachusetts Institute of Technology.

She described her research using zebrafish to study early development and cancer. Her efforts, in collaboration with scientists at Harvard Medical School, “have shown that many of the same oncogenes and tumor suppressor genes that cause cancer in mice and humans can also cause cancer when introduced or mutated in fish,” Dr. Hopkins explained. In some instances, zebrafish have advantages over the more common mouse models, she said, because fish tumors contain an abnormal number of chromosomes, which is common in human tumors but not in mice.

Despite the importance of animal research, NIH supports the development of alternatives to animal testing, Dr. Rockey said. For example, the Biological Models and Materials Research Program funds extramural research and development of non-mammalian models for biomedical research. And the National Library of Medicine offers an extensive online bibliography of resources on alternatives to live vertebrates for biomedical research and testing.

“Although for the time being, animal testing is essential to ensure the development of safe drugs, medical devices, food additives, and biological products for humans and animals, FDA and other federal agencies are aggressively moving towards reducing animal use,” explained Dr. David Jacobson-Kram, associate director of pharmacology and toxicology at the FDA. One such effort, he noted, is the International Conference on Harmonization, a collaborative project that involves regulatory officials and pharmaceutical representatives from the United States, Europe, and Japan.

Genomic biomarkers that predict carcinogenicity, Dr. Jacobson-Kram added, will lead to development of assay platforms and test protocols that enable the early prediction and mechanistic assessment of carcinogens. “It is my firm belief that we will ultimately eliminate the need for animal studies,” he said.

—Bill Robinson

FDA Update

Labeling Change Includes Warning for a Class of Prostate Cancer Drugs

The FDA has announced drug labeling changes for gonadotropin-releasing hormone (GnRH) agonists, a class of drugs used to treat prostate cancer. The changes add warnings about the potential risk of cardiovascular events and diabetes in men treated with these androgen deprivation therapy drugs.

In May, the FDA said that a preliminary and ongoing analysis found that patients receiving GnRH agonists were at a slightly increased risk for diabetes, heart attack, stroke, and sudden death. In its latest announcement, the FDA noted that health care professionals should evaluate patients for risk factors for these diseases and that patients who are receiving treatment with these drugs should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin.

GnRH agonists are marketed under the brand names Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex. Several generic products are also available.

Dasatinib Approved as First-line Treatment for Chronic Myelogenous Leukemia

The FDA has granted accelerated approval for dasatinib (Sprycel) as a first-line treatment for patients with chronic phase chronic myelogenous leukemia (CML), the agency announced last week. Like two other therapies already approved to treat CML, imatinib (Gleevec) and nilotinib (Tasigna), dasatinib targets the molecular driver of CML, a fusion of the genes BCR and ABL. This fusion gene produces a protein that spurs the overdevelopment of white blood cells that is the hallmark of CML.

The accelerated approval was based on clinical trial results reported at the American Society of Clinical Oncology annual meeting in June. The results showed that, after 12 months of follow-up, patients who received dasatinib had higher rates of complete response than patients who received imatinib. Under accelerated approval, the FDA can approve a drug that, based on the available data, the agency believes will address an unmet medical need. Under the approval, Bristol-Myers Squibb, which manufactures dasatinib, is required to collect longer-term efficacy and safety data on the drug.

Dasatinib was already approved by the FDA to treat CML patients who do not respond to or who develop resistance to other therapies, including imatinib.

Trastuzumab Becomes First Targeted Therapy Approved for Stomach Cancer

The FDA has also approved trastuzumab (Herceptin) for the treatment of stomach cancer. The approval covers the use of trastuzumab in combination with chemotherapy in patients with metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors overexpress the HER2 protein.

The decision makes trastuzumab the first targeted therapy for stomach cancer, a disease for which there have been few treatment advances over the past 2 decades. The FDA’s decision was based on results from the nearly 600-patient ToGA trial, in which patients whose tumors were HER2-positive received trastuzumab in combination with chemotherapy (cisplatin and either capecitabine or fluorouracil) or chemotherapy alone.

Results from the trial published last August in The Lancet showed a 2.7-month improvement in median overall survival for patients in the trastuzumab arm. According to the FDA, an updated analysis found a 2.4-month survival improvement, with patients whose tumors tested most strongly for HER2 overexpression by immunohistochemistry receiving the most robust survival benefit.

Notes

In Memoriam: Joan Mauer, Chief of NCI’s Clinical Trials Monitoring Branch

Joan Mauer Joan Mauer

Joan Mauer, chief of the Clinical Trials Monitoring Branch (CTMB) of NCI’s Cancer Therapy Evaluation Program (CTEP), died at her home in Virginia on October 10. She is credited with implementing many processes that have improved and protected the safety and integrity of clinical research studies during her 27 years at NCI.

Mauer joined NCI’s Division of Cancer Treatment and Diagnosis in 1982 and led the Quality and Assurance Section during the 1990s. As chief of CTMB, she headed the program that provides guidance and oversight of the quality assurance and monitoring programs of NCI Cooperative Groups, cancer centers, and phase I clinical trials.

Associate Director of CTEP Dr. Jeff Abrams remarked, “Joan was an especially talented public servant, capable of ensuring high standards for clinical research, yet always able to do this with an endearing, personal touch. We will miss her tremendously.”

NCI to Co-host Scientific Journalism Workshop in Rio de Janeiro

NCI and five national cancer research organizations in Latin America will convene the inaugural “Cancer Research in the Media: Inter-American Workshop for Scientific Journalism” on November 11 and 12 in Rio de Janeiro, Brazil. Journalists from Argentina, Brazil, Chile, Mexico, Uruguay, and the United States will participate in the workshop to discuss health and science, and in particular cancer. The aim is to increase participants’ awareness and understanding of cancer-related topics. The workshop will feature scientific speakers representing a broad spectrum of cancer expertise.

Session themes will include:

  • Cancer research in the laboratory
  • Cancer research in the clinic
  • New technologies used in cancer research
  • Challenges and opportunities in communicating science to the public
  • Evaluating cancer research studies
  • Analyzing and grading coverage of cancer research news