National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
April 21, 2009 • Volume 6 / Number 8

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Cancer Research Highlights

Combination Therapy Targets Pancreatic Cancer Stem Cells

Logo for the American Association for Cancer Research 100th Annual Meeting 2009 A new drug combination tested in mice may target the cells responsible for driving some pancreatic tumors. The combination of gemcitabine and the experimental drug tigatuzumab eliminated populations of cancer stem cells and reduced tumor growth in a mouse model of pancreatic cancer, researchers from the Johns Hopkins Sidney Kimmel Cancer Center reported at the AACR annual meeting.

The results provide a rationale for testing the promising combination in patients with this deadly disease, Dr. Rajesh Kumar NV and his colleagues concluded.

Cancer stem cells are thought to self renew while giving rise to tumors, and they may resist conventional treatments. The researchers found that human pancreatic cancer stem cells overexpress a protein called death receptor-5 (DR-5), which is involved in programmed cell death (apoptosis). The protein is also the target of tigatuzumab, a humanized monoclonal antibody also known as CS-1008.

To evaluate the drug’s effects on these important cells, mice were given tigatuzumab alone, gemcitabine alone, or a combination. Although gemcitabine reduced tumor size, it increased levels of pancreatic cancer stem cells (as defined by the protein markers ALDH, CD24, and CD44), and all of the tumors recurred. The combination treatment, however, led to long-term remissions in half of the treated mice.

In addition, cancer stem cells were eliminated in mice that received tigatuzumab plus gemcitabine, which is the first-line treatment for patients with advanced pancreatic cancer. “It appears that tigatuzumab may be one of the first monoclonal antibodies to target cancer stem cells,” said Dr. Kumar NV. The drug is being tested in a phase II clinical trial with patients who have inoperable, untreated pancreatic cancer.

Potential Treatment for Brain Cancer Identified

Researchers have identified a potential drug for treating brain cancer that appears to have effects on both tumors and the growth of blood vessels (angiogenesis) that provide essential nutrients and oxygen to the tumors. Growing evidence suggests this strategy may be important for treating glioma brain tumors, as it is for other cancers. In preclinical studies, the compound, 2.5-dimethyl-celecoxib, crossed the blood-brain barrier and inhibited both tumors and angiogenesis.

“Here you have a single drug that attacks both tumor cells and tumor blood vessels, and it can be used over the long term,” said Dr. Florence Hofman of the University of Southern California Keck School of Medicine. The drug is not a COX-2 inhibitor, a family of drugs that has been associated with prohibitive side effects, and therefore it could potentially be used over several years rather than months.

While dimethyl-celecoxib is not expected to be a cure for brain cancers, the drug or a similar agent could extend survival for patients with this deadly disease by up to several years, the researchers said Sunday at the AACR annual meeting. They suggest that it may also have potential to treat tumors that spread to the brain and depend on the growth of blood vessels.

“We’re learning that the blood vessel target is critical in treating this cancer,” said Dr. Hofman. “And we think that our way of getting at the target has advantages over other approaches.”

Filter Captures Tumor Cells from Blood

A novel device employing a “membrane microfilter” can process blood and capture circulating tumor cells (CTCs), or cells that have escaped from a tumor into the circulatory system, researchers from the University of Southern California Keck School of Medicine and the California Institute of Technology said Sunday at the AACR annual meeting.

Circulating tumor cells have emerged as a potential “surrogate biopsy” for metastatic disease, and there is a growing need for noninvasive methods, such as capturing these cells, to diagnose and monitor cancer, noted Anthony Williams, a graduate student at the Keck School of Medicine who described the device in a press briefing. While the technology is not commercially available, the researchers said that it will be used in several upcoming clinical trials to monitor patients.

The device exploits differences in the sizes of normal and cancer cells. “Circulating tumor cells are larger than their normal counterparts,” said Williams. “The pore sizes on the filter allow normal-sized blood cells to pass through, while it captures the larger tumor cells.” Compared to other technologies, which can take hours to analyze a sample, the microfilter device is relatively fast, producing a result for certain samples in a matter of minutes.

Using Veridex’s CellSearch system, the only FDA-cleared device for CTC detection and enumeration, researchers are already investigating whether cancer patients’ CTC levels can be used to direct therapy. The microfilter device used in this study detected CTCs in approximately 93 percent of blood samples taken from nearly 60 advanced cancer patients, compared to only 46 percent when the CellSearch system was used on the same samples.

The research team plans more studies with the device to determine whether levels of CTCs can be used as early indicators of treatment efficacy, as well as to molecularly characterize captured CTCs for the identification of therapeutic targets.

Markers for Chronic Lymphocytic Leukemia Found in Blood

The blood of patients with chronic lymphocytic leukemia (CLL) may contain protein abnormalities that can be detected years before the disease is diagnosed, researchers said at the AACR annual meeting. An analysis of blood samples obtained up to a decade prior to a diagnosis of CLL revealed disruptions to the immune system in certain patients. In addition to providing clues to the biology of the disease, the findings provide a rationale for exploring whether prediagnostic changes in immune function have an effect on CLL prognosis, the researchers said.

To make the discovery, Dr. Huei-Ting Tsai of NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and her colleagues obtained prediagnostic blood samples from 109 people who developed the disease over the course of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. This NCI-sponsored trial has serial blood samples from more than 77,000 people.

About 40 percent of patients who eventually developed CLL had evidence of immune disruption prior to diagnosis. In addition, 31 percent had a skewed free light chain (FLC) ratio, which is a measure of immune disruption. This change was evident in one patient 9.8 years prior to diagnosis.

The finding that CLL is often preceded by an altered FLC ratio points to infection or other immune changes as areas to investigate further, said coauthor Dr. Neil Caporaso of DCEG. “This is an important clue as we focus efforts on understanding the environmental, molecular, and genetic factors associated with that condition.” 

Little is know about the causes of CLL, though it is linked with family history and aging. With the prediagnostic samples, the researchers could distinguish between alterations that developed because of the disease and those that were present before the leukemia arose. “We were fortunate to have access to the PLCO samples so that we could look back in time to detect the protein abnormalities in this mysterious disease,” noted Dr. Tsai.

In February, these researchers used PLCO blood samples to discover that a precursor state called monoclonal B-cell lymphocytosis was evident years before a diagnosis of CLL. Together, these findings illustrate the power of cohort studies to clarify precursor states for cancer, the researchers said.

ALSO IN THE JOURNALS

Survivors of Hereditary Retinoblastoma Face Second Cancers Later in Life

Children who survive hereditary retinoblastoma, a rare cancer of the eye, have an increased risk of death from a second cancer later in life. The largest study to date of hereditary retinoblastoma survivors found that by 50 years after treatment, 1 in 4 survivors with the inherited form of the disease had died of a second cancer, whereas only 1 percent of survivors with nonhereditary retinoblastoma had died of second cancers. These included primarily bone and soft tissue sarcomas, melanomas, and cancers of the brain and central nervous system, as well as lung and uterine cancers.

Retinoblastoma, which involves mutations in the tumor-suppressor gene RB1, is diagnosed in about 300 children in the United States each year, most of them under the age of 5. In Western countries, the vast majority of children survive hereditary retinoblastoma, as well as the nonhereditary form of the disease.

Following up a previous report, Dr. Chu-Ling Yu of NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and her colleagues identified the causes of death for 1,092 survivors of hereditary retinoblastoma and 762 survivors of nonhereditary retinoblastoma who were diagnosed between 1914 and 1996. The mortality rate due to second cancer was 35-fold higher in the hereditary retinoblastoma survivors and 2.5-fold higher in the survivors of nonhereditary retinoblastoma, compared with the general population.

Both the genetic predisposition of these patients to cancer as well as treatment with radiation likely contributed to the development of a second cancer in those with hereditary retinoblastoma, noted senior author Ruth Kleinerman of DCEG.

“It’s important for physicians who care for survivors of this cancer to be aware that even with the excellent survival rates, patients with hereditary retinoblastoma are at greatly increased risk of developing a new malignancy later in life,” said Ms. Kleinerman.

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