Cancer Research Highlights
Mapping the Molecular Changes in Colorectal Cancer
A molecular analysis of colon and rectal tumors has yielded insights that could lead to more targeted treatments for patients with this disease, according to a report by investigators from The Cancer Genome Atlas (TCGA) Research Network. Their findings are publicly available (here and here) and summarized in Nature this month.
TCGA investigators have previously reported on the molecular changes underlying ovarian cancer and glioblastoma, an often deadly brain cancer. In the new analysis, the researchers comprehensively characterized the genomes of 224 colon or rectal tumors, as well as matched normal DNA from the donors.
After excluding from their analysis tumors that had abnormally high rates of genetic mutation (hypermutated tumors), the researchers found no significant genomic differences between colon and rectal tumors, based on a variety of measures, including the number of copies of genes and the gene expression profiles of the tumors.
But an analysis of the molecular pathways in colorectal tumors showed that pathways could be disrupted in a number of ways. Some tumors had potentially cancer-related changes in multiple pathways, suggesting to the researchers that targeting a single pathway would not be sufficient to treat these tumors.
Most of the approved treatments for colorectal cancer are chemotherapies that produce poor response rates, noted Dr. Raju Kucherlapati of Harvard Medical School, who co-led the study. The new findings could form the basis for developing and testing therapies that target the molecular changes driving the disease, he added.
“There are a number of genetic changes present [in the tumors we examined], and drugs that target many of these changes are already in development,” Dr. Kucherlapati continued. For selected patients, new targeted drugs “have the potential to be highly effective.”
He and his colleagues in the TCGA Research Network also found that 16 percent of the tumors were hypermutated. This phenomenon may be caused by defects in a cell’s ability to repair damaged DNA. Hypermutated tumors may also be aggressive.
Three-quarters of the specimens had a genetic change called microsatellite instability, which is associated with a better prognosis.
The researchers also found that the gene IGF2, which plays a role in cell proliferation, was altered in some tumors. Drugs that target the product of this gene or its receptor are in development and could be tested in patients whose tumors have alterations in IGF2.
The data from this study “provide an unprecedented resource for understanding this deadly disease and identifying possibilities for treating it in a targeted way,” the authors concluded.
This research was supported by grants from the National Institutes of Health (U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079, and U54HG003273).
Drug May Make Bone Marrow Transplants to Treat Blood Cancers Safer
Results from a small clinical trial suggest that a drug used to treat HIV infection may help prevent a potentially lethal complication of bone marrow transplants to treat patients with blood cancers. The drug, maraviroc, appears to work by altering the activity of immune system cells that are chiefly responsible for graft-versus-host disease (GVHD). The findings were published July 12 in the New England Journal of Medicine.
Allogeneic stem cell transplantation is often required to treat patients with leukemia and lymphoma. GVHD occurs when immune cells in the transplanted cell population attack the patient’s body, typically organs such as the liver, skin, and gut.
Dr. Ran Reshef of the University of Pennsylvania Abramson Cancer Center and his colleagues conducted a 38-patient clinical trial to test whether a 33-day course of maraviroc might limit or prevent GVHD. The drug targets a receptor on certain immune cells that helps direct them as they move throughout the body.
Overall, 35 patients could be evaluated, all of whom underwent reduced-intensity conditioning stem cell transplants. In this procedure, lower doses of drugs are used to kill cancer cells and suppress immune cells in the patients’ bone marrow before they receive stem cells. The 35 patients also received maraviroc and two other drugs commonly used to prevent or limit GVHD.
Six months after the transplants, about 6 percent of patients had experienced serious GVHD (grade III and IV)—more than 70 percent lower than what is usually seen after reduced-intensity-conditioning transplants, the authors reported. The treatment was most effective at preventing GVHD in the liver and gut, which can produce debilitating and even fatal outcomes.
In the first 100 days after the transplants, no patient had GVHD in the liver or gut; 6 months after the transplants, the rates were approximately 3 percent and 9 percent, respectively, which Dr. Reshef noted “is still very low.”
The rates of cancer relapse and death were nearly identical to what is typically seen with reduced-intensity conditioning transplants, a finding that Dr. Reshef said supports the hypothesis that maraviroc does not significantly suppress the immune system. “Disease relapse is a major concern of any trial of GVHD prevention,” he explained. “You may reduce GVHD, but you can pay the price of increased relapse. We were encouraged that we did not see this in our trial.”
More studies are needed to better understand the drug’s impact, Dr. Reshef stressed. The Abramson team is planning another small trial to test a longer course of maraviroc treatment, and they have begun discussions with the NCI-supported Blood and Marrow Transplant Clinical Trials Network to conduct a larger, multicenter trial.
This research was supported in part by the National Institutes of Health (P30-CA16520, K24-CA117879, and U01-HL069286).
Tumors May Resist Cancer Drugs with Help from Neighboring Cells
Researchers have identified a protein secreted by nontumor cells that may help nearby tumors evade the effects of anticancer drugs. The results, published online in Nature on July 4, add to a body of evidence that interactions between cancer cells and surrounding cells in the tumor microenvironment may influence the growth of tumors and their responses to treatments.
Patients with cancer rarely have complete responses to targeted drugs, and this suggests that there are mechanisms that can render a substantial proportion of tumor cells innately resistant to therapies. Although genetic mutations that allow tumors to acquire resistance over time have been identified, less is known about sources of innate resistance.
To identify nontumor sources of innate resistance, Dr. Todd Golub of the Broad Institute and his colleagues grew cancer cells along with cells from the body’s connective tissue, or stroma, in the lab. When they exposed these mixtures of stromal cells and cancer cells to targeted anticancer drugs, the cancer cells were resistant to 15 of the 23 agents evaluated.
An analysis of more than 500 factors secreted by noncancer cells indicated that a protein called hepatocyte growth factor (HGF) may make melanomas with BRAF gene mutations resistant to treatment with vemurafenib, a recently approved drug that targets BRAF-mutated melanoma cells.
When the authors tested 34 samples from patients with melanoma, they found a correlation between HGF levels and the amount of tumor shrinkage following vemurafenib treatment. They also found evidence of resistance mediated by the microenvironment in other cancers.
Several drugs that inhibit HGF or MET, the receptor on tumor cells for HGF, are in development or have been approved for other indications, the authors noted. Combination clinical trials in BRAF-mutant melanoma, colorectal cancer, and possibly other tumor types could be considered, they added.
“It is increasingly recognized that both the tumor and its microenvironment will need to be therapeutically targeted for maximum efficacy,” commented Dr. Dinah Singer, director of NCI's Division of Cancer Biology. “This study provides an explicit example of a therapeutic strategy to address this.”
Understanding the role of the tumor microenvironment in the initiation, progression, and spread of cancer, Dr. Singer added, is a goal of the Tumor Microenvironment Network, an initiative sponsored by NCI.
This research was supported in part by the National Institutes of Health (P50-CA093683 and U54-CA112962).