In the Jan. 4 advance online publication of Nature Medicine, two NCI research groups reported their identification of two important proteins involved in metastasis.
In the first study, NCI's Dr. Yanlin Yu, Dr. Javed Khan, and colleagues used microarray-based expression profiling of highly and poorly metastatic rhabdomyosarcoma cell lines. This analysis identified two genes, ezrin and the developmental transcription factor Six-1, as playing central roles in metastasis. Ezrin links the cell membrane with the actin cytoskeleton, thereby allowing a cell to interact with its microenvironment. It had previously been implicated in metastasis based on its role in signal transduction. Six-1 had previously been reported as a cell cycle regulator.
The researchers verified their findings in vivo by injecting cells that overexpress ezrin and Six-1 into nude mice. Though Six-1 was shown to increase tumor cell proliferation and invasiveness in vitro, the pathway by which it influences metastasis remains to be elucidated.
In the second study, led by Dr. Chand Khanna of NCI, ezrin was found to be necessary for osteosarcoma metastasis as well. The authors' findings were based on studies in mouse and dog models, as well as examination of tissue from pediatric osteosarcoma patients. The researchers suggested that ezrin played multiple roles in early metastasis and might therefore be a potential target for future antimetastatic therapies.
A revision of the criteria for diagnosing individuals with Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), will be announced in the Feb. 18 issue of the Journal of the National Cancer Institute (JNCI). HNPCC is an autosomal dominant - only one parent must have an abnormal gene on one of the autosomal chromosomes in order for the child to inherit the disease - type of cancer predisposition syndrome that is characterized by early onset (typically before age 45 years), the development of neoplastic lesions in a variety of tissues, and microsatellite instability (MSI), a term used to describe mutations in short repetitive sequences of DNA.
The update of the guidelines is based on findings presented at an international workshop on Lynch syndrome (HNPCC) and MSI held at NCI in 2002. The recommendations for determining populations that should be screened by MSI testing were based on factors including age, familial history, genetic analysis, and the biochemical nature of detected tumors. MSI in colorectal cancers is caused by mutations in DNA repair genes, and it has been estimated that 15 percent of all colorectal cancers have MSI.
The guidelines are a revision of those developed at a meeting in Bethesda in 1996. These guidelines include criteria for identifying colorectal tumors that should be tested for mutations in one of the DNA mismatch repair genes. This testing provided information on the performance, specificity, and sensitivity of the guidelines, which was then used to form the revised Bethesda Guidelines. "With recent advances in biochemistry and genome sequencing, it became obvious to us that we had to revisit the Bethesda Guidelines," explained Dr. Asad Umar of NCI's Division of Cancer Prevention, organizer and first author of the JNCI report. "Now that we know the nature of the genes involved in microsatellite instability, our next step is to focus more on understanding the actual molecular defects involved in these processes."
Researchers from Creighton University reported last week that they identified a hereditary genetic mutation that "may turn out to account for a significant proportion" of cases of HNPCC in the United States. In the NCI-funded study, published in the Feb. 11 Journal of the American Medical Association, the research team analyzed the genealogical history of nine families with a history of HNPCC from distinct geographic areas of the United States. They identified 61 family members from 14 states with an identical mutation in the MSH2 gene. The mutation is the first HNPCC "founder mutation" in a large, outbred population in the United States, said study co-author Stephanie M. Coronel.
Of the approximately 950,000 new cases of colorectal cancer worldwide each year, 10 percent are estimated to be hereditary. HNPCC is the most common form of hereditary colorectal cancer, and individuals with HNPCC are also at extremely high risk of a number of other cancers, including endometrial and ovarian.
In a person with a founder mutation, his or her offspring have a 50 percent chance of inheriting the mutation. Cases of breast cancer among Ashkenazi Jews, for example, are the result of founder mutations in the BRCA1 and BRCA2 genes. Although genetic screening "is becoming a standard of care" in people from families with a history of HNPCC, the researchers explained that, in this study, the standard genetic sequencing "and other commonly used genetic testing methods" performed poorly in detecting the mutations identified in the 61 individuals.
"An assay for this specific mutation should be added to routine MSH2 testing in the United States," the researchers concluded. "Previously tested families with HNPCC for which no mutation was found should be retested for this specific mutation."
In related news, researchers from the NCI Division of Cancer Prevention and the NCI Center for Cancer Research have published an overview of revised Bethesda Guidelines for testing HNPCC in the Feb. 18 issue of the Journal of the National Cancer Institute (JNCI).
The Food and Drug Administration (FDA) last Thursday approved cetuximab (Erbitux®) for use in conjunction with irinotecan-based chemotherapy to treat patients with refractory metastatic colon cancer. The approval is primarily based on the results of clinical trial data that showed treatment with cetuximab and irinotecan shrank tumors in more patients and delayed tumor progression longer than cetuximab alone. Cetuximab is a monoclonal antibody that targets epidermal growth factor receptor (EGFR), a protein on the surface of cancer cells that promotes tumor growth.
"Cetuximab has now been shown to benefit patients who have not responded to irinotecan-based chemotherapy. The FDA should be commended for moving decisively to get this drug to market," said NCI Director Dr. Andrew C. von Eschenbach.
According to an FDA news release, Erbitux was approved under the FDA's accelerated approval program, which allows the FDA to approve products for cancer and other serious or life-threatening diseases based on early evidence of a product's effectiveness.
In a 329-patient phase II clinical trial for metastatic colorectal cancer presented last June at the American Society of Clinical Oncology meeting, the combination therapy shrank tumors in 22.9 percent of patients who had not responded to chemotheraphy, while cetuximab alone shrank tumors in 10.8 percent of patients. Tumor progression occurred at a median of 4.1 months in the combination therapy group, compared to 1.5 months in the group receiving cetuximab alone. The trial found a statistically insignificant increase in survival time, and severe side effects were more frequent among patients receiving the combination therapy.
The NCI Cancer Therapy Evaluation Program is currently sponsoring a series of trials to assess cetuximab's effectiveness for other indications, including a phase III trial for patients with newly diagnosed metastatic colorectal cancer and several early trials combining cetuximab with other investigational agents.
The FDA also is currently reviewing the potential use of the monoclonal antibody bevacizumab (Avastin®) as a first-line treatment in patients with advanced colorectal cancer.