National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 12, 2010 • Volume 7 / Number 1

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Cancer Research Highlights

Study Weighs Comparative Effectiveness of Low-risk Prostate Cancer Treatments

When it comes to the treatment of low-risk prostate cancer, a new comparative effectiveness study has concluded that the various approaches—including active surveillance, surgery, and radiation therapy—result in similar overall survival and tumor recurrence rates. However, compared with the immediate treatment options, active surveillance yields both a comparable net health benefit and more quality-adjusted life years for men age 65 and older, according to the economic model used in this study.

Researchers at the Institute for Clinical and Economic Review, which is based at the Massachusetts General Hospital’s Institute for Technology Assessment, examined the published evidence on different approaches being used to manage low-risk prostate cancer and the results of a simulation model that can project the long-term effects of each approach for large populations. Their review also included a comparison of the relative economic cost of each approach. The literature review and analysis were aided by an evidence review group of nearly 50 members that included top prostate cancer specialists from across the country, patient advocates, and representatives from medical device, pharmaceutical, and health insurance companies.

Their task was complicated, the reviewers acknowledged, by a lack of published trials that compared the different options head-to-head, as well as other factors. In addition to traditional open surgery (or radical prostatectomy), they assessed the clinical and cost effectiveness of robotic and traditional laparoscopic prostatectomy, as well as of brachytherapy and intensity-modulated radiation therapy. Because of the limited published data on proton beam radiation therapy, a treatment for localized prostate cancer that has gained popularity, the reviewers called it “premature” to offer any “judgments about its relative benefit or inferiority to other options.”

Lenalidomide Helps Delay Progression of Multiple Myeloma

Initial results from a phase III trial testing lenalidomide (Revlimid) as a component of multiple myeloma treatment indicate as much as a 58 percent reduction in the risk of disease progression for patients who used the drug, according to a news release issued by NCI. The trial was stopped early because the independent data and safety monitoring committee overseeing the trial found that the study demonstrated a longer time before the cancer progressed following autologous blood stem cell transplantation for those patients receiving the study drug than those receiving a placebo.

Lenalidomide was developed as a more potent yet safer version of thalidomide, and it has been approved by the FDA to treat myelodysplastic syndromes. The drug has also been used as a first-line induction therapy for multiple myeloma, a cancer that begins in plasma cells. Following induction therapy, myeloma patients typically receive autologous stem cell transplantation, which, if successful, may be followed by use of another drug as maintenance therapy to prevent disease recurrence or progression.

In this clinical trial (CALGB-100104), between 100 and 110 days after successful treatment with melphalan and transplantation of the patient’s own stem cells, which were harvested prior to chemotherapy, 460 patients who had no progressive disease were randomly assigned to receive lenalidomide or a placebo and took the drug until their disease began to progress. Most of the patients who received lenalidomide showed no evidence of progressive disease, while progression occurred in half of those taking a placebo within 778 days. Because of the trial’s early termination, there is no proof yet of an overall survival benefit.

“This study answers the important question for multiple myeloma patients regarding maintenance lenalidomide therapy starting at 100 days following transplant,” said the trial’s principal investigator Dr. Philip L. McCarthy, Jr., of Roswell Park Cancer Institute and the Cancer and Leukemia Group B. “We now know that prolonged maintenance therapy with lenalidomide when compared to placebo will delay disease progression.”

The Eastern Cooperative Oncology Group and the Blood and Marrow Transplant Clinical Trials Network also participated in this research.

Genetic Study of Lymphoma Tumors Points to Possible Therapies

A genetic study of lymphoma tumors has revealed the importance of a signaling pathway long suspected of playing a role in certain forms of the disease. DNA mutations were found in two components of the B-cell receptor signaling pathway in a subset of patients with diffuse large B-cell lymphomas (DLBCL). In additional experiments, the researchers showed that drugs could kill these lymphoma cells by blocking signals from this pathway.

Reporting their findings January 7 in Nature, Dr. Louis Staudt of NCI’s Center for Cancer Research and his colleagues estimate that the mutations are present in approximately one-fifth of the activated B-cell-like (ABC) subtype of DLBCL. Although the mutations are rare or nonexistent in the other subtypes, they appear to be important in the development of the disease for those patients who harbor the mutations.

The mutations affect two components of the B-cell receptor—the proteins CD79B and CD79A. DLBCL originates in B cells, which are part of the body’s immune system. When normal B cells encounter a foreign substance, proteins on the cell surface called B-cell receptors activate a cascade of signals that help the cell to survive and proliferate. In tumors with the mutations, the researchers observed “chronic active” B-cell receptor signaling, in which the tumor cells spontaneously activated this pathway.

“We have found mutations that affect a key signaling pathway in certain lymphoma tumors, and these mutations represent a genetic smoking gun that reveals the importance of this pathway in this type of cancer,” said Dr. Staudt. The findings suggest that future clinical trials of agents targeting this pathway should focus on patients with ABC DLBCL, he added.

In laboratory experiments, several compounds selectively killed lymphoma cells with chronic active B-cell receptor signaling, including dasatinib (Sprycel), which is approved for treating chronic myelogenous leukemia. The drug turned off the signaling pathway by inhibiting a component of it, and, as a result, the mutant cells died, the researchers said.

“This is a fascinating and elegant paper,” wrote immunologist Dr. Klaus Rajewsky of Harvard Medical School in an e-mail message. “A role for the B-cell receptor in lymphoma development, progression, and maintenance has long been suspected, and it will be interesting to see whether other signaling cascades downstream of this receptor contribute to these processes in other contexts.”

Vaccine Kills Residual Leukemia Cells in Patients Treated with Imatinib

In an early phase clinical trial testing a therapeutic vaccine in patients with chronic myeloid leukemia (CML) who were taking the drug imatinib (Gleevec), no cancer cells could be detected in 7 out of 19 participants for a median period of 22 months. The trial results were published in the January 1 Clinical Cancer Research.

Although imatinib has greatly improved survival for patients with CML, in most cases it does not entirely eradicate cancer cells in the body. Residual cancer cells can eventually cause a relapse.

The experimental vaccine was constructed from a CML cell line engineered to express a protein called granulocyte-macrophage colony-stimulating factor (GM-CSF), which helps draw immune cells to the site of the vaccination. These immune cells then encounter proteins (called antigens) found on the surface of the engineered CML cells. The researchers, led by Dr. B. Douglas Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, hoped that, after encountering the antigens, the immune cells would be able to locate and kill CML cells elsewhere in the body.

Nineteen patients with chronic-phase CML enrolled in the trial; all of them had been taking imatinib (for a median of 37 months) but still had measurable tumor cells in the body. Patients continued to take imatinib during the trial. All patients received four vaccinations spaced 3 weeks apart. Side effects were mostly mild, although three patients experienced painful reactions at their injection sites.

After a median of 33 months of follow-up, 74 percent of the patients had a major molecular response (a major reduction in the number of CML cells in the bloodstream), and 37 percent had a complete molecular response (no CML cells detectable). CML cells remained undetectable in several patients at the time of publication (between 20 and 44 months after vaccination).

The researchers are planning a follow-up trial to determine if the benefits of immunotherapy persist after patients stop taking imatinib.

Cancer Cells Use Stored Fats to Fuel Aggressive Growth and Spread

An enzyme that is best known for breaking down stored fats in cells may be co-opted by cancer cells so that they can become more aggressive, Scripps Research Institute investigators have reported. Blocking the activity of the enzyme, MAGL, in cell lines of several aggressive cancers and in mouse models derived from the cell lines significantly tempered cell migration and tumor growth, Dr. Daniel Nomura and colleagues reported January 8 in Cell.

In the same mice in which MAGL levels were reduced, the research team found that a high-fat diet could kick start tumor growth. This latter finding, they wrote, “has provocative implications for the crosstalk between obesity and tumorigenesis.”

To conduct the study, the researchers first analyzed the expression of certain types of enzymes in cell lines of aggressive and non-aggressive melanoma, breast, and ovarian cancer. They found that MAGL levels were significantly elevated in the aggressive cell lines. They also found that when they increased MAGL levels in the non-aggressive cancer cell lines, the cancer cells became more aggressive.

MAGL promotes this aggressive posture in cancer cells, the researchers discovered, by unleashing free fatty acids (FFAs), which are integral components of cell membranes and other molecules in cells. The increased production of FFAs, in turn, stimulates the activity of a communication network of signaling lipids known to enhance the growth of tumors and movement of cancer cells. In the mice with inhibited MAGL expression fed a high-fat diet that led to increased tumor growth, the researchers noted, the tumors had significantly elevated levels of FFAs.

The study’s findings provoke “many exciting new questions,” wrote Drs. Jessica Yecies and Brendan Manning from the Harvard School of Public Health in an accompanying editorial. Among them is whether MAGL levels could “be used as a biomarker to predict the influence of dietary fats and obesity on tumor progression.”

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