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Interferon-gamma Promotes UV-Induced Melanoma in a Mouse Model

Posted Jan 25 2011 12:00am

Trial Suggests New Treatment Option for Gastrointestinal Stromal Tumors

The targeted therapy sorafenib (Nexavar) may be a treatment option for patients with gastrointestinal stromal tumors (GIST) whose cancers no longer respond to two FDA-approved therapies, researchers reported last week at the 2011 Gastrointestinal Cancers Symposium in San Francisco.

In a 38-patient phase II clinical trial, 13 percent of patients whose tumors had developed resistance to imatinib (Gleevec) and sunitinib (Sutent) had a partial response (tumor shrinkage of 50 percent or more) after taking sorafenib, and 55 percent experienced disease stabilization (no further tumor growth) with the drug. Median progression-free and overall survival was 5.2 and 11.6 months, respectively. After 1 year, 44 percent of patients were still alive; after 2 years, survival had dropped to 21 percent.

Sorafenib has multiple molecular targets, including mutated forms of several tyrosine kinases—disregulated forms of which are implicated in a number of cancers—that are known to be insensitive to imatinib and sunitinib, explained the trial’s lead investigator, Dr. Nicholas Campbell from the University of Chicago, during a press briefing. The trial protocol was amended early on to require that participants have GIST that is resistant to both imatinib and sunitinib. Overall, six patients in the trial were resistant to imatinib and 32 were resistant to both.

More than 60 percent of the patients in the NCI-supported trial had to have their sorafenib dose reduced because of side effects, including large increases in blood pressure and serious skin rashes , although reducing the dose did not appear to alter the drug’s efficacy, Dr. Campbell added.

The results show that sorafenib has “definite clinical activity” in patients with GIST whose tumors have developed resistance to imatinib and sunitinib, he concluded, adding that further studies of sorafenib as a therapy for GIST are warranted. An exploratory analysis of patients in the trial is being conducted to determine whether mutations in two tyrosine kinases, PDGF and KIT, correlate with response to sorafenib.

Gene Test for Risk of Colorectal Cancer Recurrence Validated

An experimental genetic test designed to assess the risk of colorectal cancer recurrence in patients with early-stage disease has been validated for a second time, researchers reported last week at the 2011 Gastrointestinal Cancers Symposium in San Francisco. The test, called ColoPrint, provides a risk score based on the activity of 18 genes. The development of the test and its initial validation are described in a report published last year.

Most patients with stage II colorectal cancer are treated with surgery alone. But about 20 percent of these patients experience a recurrence and could potentially benefit from adjuvant (post-surgical) chemotherapy to reduce this risk. The new study showed that the gene classifier test could “facilitate the identification of patients who might not need chemotherapy,” said Dr. Robert Rosenberg of the University Hospital at the Technical University, in Munich, Germany, during a press briefing. The study was funded in part by Agendia, the manufacturer of the test.

Previous attempts to use pathologic and clinical factors to predict prognosis have been unsuccessful. In the current study, the researchers used the ColoPrint test to analyze tumor tissue from 233 patients who had undergone surgery for stage II or stage III colorectal cancer at the University Hospital in Munich. Based on patterns of gene activity in the tumors, the gene classifier produces a score indicating low or high risk of recurrence.

The researchers then compared the risk scores of the 135 stage II patients with their outcomes. The gene classifier identified 73 percent of the stage II patients as low risk, and 5 percent of this group experienced a recurrence within 5 years or more. The test identified the remaining 27 percent of stage II patients as high risk, and 20 percent of these patients did have a recurrence during a median follow-up period of more than 8 years. The performance of the gene classifier seemed to be independent of clinical risk factors, Dr. Rosenberg explained.

A third validation study, the PARSC (Prospective Analysis of Risk Stratification by ColoPrint) trial, has been launched. This trial, which is sponsored by Agendia, will address the feasibility of using the gene classifier in clinical practice and test whether the ColoPrint assay offers a more accurate risk assessment for recurrence than commonly used clinical parameters.

Newly Discovered Mutations May Help Drive Common Kidney Cancer

Researchers have discovered mutations in a gene called PBRM1 in more than one-third of clear-cell renal cell carcinomas (ccRCC), the most common kind of kidney cancer . In a series of experiments led by Dr. Ignacio Varela of the Wellcome Trust Sanger Institute, an international team of researchers identified PBRM1 as a potential tumor suppressor gene and showed that the loss of the gene’s function may contribute to kidney cells developing the properties of cancer cells, such as uncontrolled cell growth. The findings appeared online January 19 in Nature.

The scientists first sequenced portions of the genome known to produce proteins (called the exome) in seven ccRCC tumor samples and normal tissue from the same patients. They identified 156 mutations in those seven samples, but only mutations in PBRM1 were found in more than one sample. They next sequenced the PBRM1 gene in an additional 257 renal cell carcinoma samples (including 36 non-ccRCC cases) and found mutations in 88 samples (all ccRCC), a frequency that the authors described as “remarkable.”

The researchers also found PBRM1 mutations in breast, lung, kidney, gallbladder, and pancreatic cancer cell lines. Analysis of genetic data from a mouse model of pancreatic cancer indicated that inactivation of the PBRM1 gene may help drive pancreatic tumor development in this model.

Using small interfering RNAs to block PBRM1 activity in ccRCC cells, the researchers were able to increase cell proliferation , cell-colony formation (the ability to grow and divide without physical support), and cell movement, like that required for metastasis . PBRM1 codes for a protein that is involved in chromatin remodeling, a process that allows transcription factors to gain access to DNA that is otherwise tightly packaged with proteins. Analysis of the cell-signaling pathways regulated by PBRM1, the authors wrote, suggests that “PBRM1 activity regulates pathways associated with chromosomal instability and cellular proliferation.” They also noted that several other genes that have been implicated in ccRCC are involved in chromatin remodeling.

“This is very promising, very exciting work,” commented Dr. Marston Linehan, chief of the Urologic Oncology Branch in NCI’s Center for Cancer Research, who was part of the scientific team that identified the tumor suppressor gene VHL, which is the only other gene known to play a role in a large number of ccRCC cases. “This finding leads us potentially into a whole new direction in thinking about the basic aspects of kidney cancer and potential approaches to therapy. It’s possible that mutations in PBRM1 are a critical part of clear-cell kidney cancer and that you need both VHL and PBRM1 to be altered to develop a clear-cell kidney cancer,” he concluded.

Interferon-gamma Promotes UV-Induced Melanoma in a Mouse Model

The immune system protein interferon -gamma may fuel melanoma in mice by promoting the growth, survival, or both of melanocytes , the pigment-producing cells in which melanoma begins. The results , from research aimed at understanding how ultraviolet (UV) radiation from the sun and other sources causes melanoma, appeared online January 19 in Nature. The finding that interferon-gamma promotes melanoma was unexpected because interferon-gamma has been thought to be part of the immune system’s innate defense against cancer.

Researchers led by Drs. Glenn Merlino and M. Raza Zaidi of NCI’s Laboratory of Cancer Biology and Genetics found that UVB radiation (UVB), at doses equivalent to what causes sunburn in human skin, triggered aberrant growth and migration of melanocytes in mouse skin. UVB exposure also persistently activated genes that are known to respond to interferon-gamma, including genes that may help tumor cells evade detection and attack by the immune system. Blocking the activity of interferon-gamma lessened the effects of UVB on the growth and migration of melanocytes.

The team showed that interferon-gamma was being produced by white blood cells known as macrophages , which traveled to the skin after UVB exposure. These macrophages significantly enhanced melanoma tumor growth when the researchers injected them under the skin of healthy mice along with cultured mouse melanoma cells, and this effect was abolished by blocking interferon-gamma activity. The researchers also identified interferon-gamma-producing macrophages in 70 percent of 27 human melanomas they examined, supporting the possibility that interferon-gamma plays a role in this type of cancer not just for mice but also for humans.

Dr. Merlino noted that treatments with high doses of interferons and other cytokines in cancer patients, which are not always effective, can be toxic and are often associated with debilitating side effects. “The new study shows that lower, physiologically relevant levels of interferon-gamma, produced by specific tumor-associated inflammatory cells, can actually support melanoma growth” in mice, he said. Thus, if this holds true in humans, “inhibition of the interferon-gamma pathway may represent a more effective, less toxic immunotherapeutic alternative for treatment of a subset of patients with macrophage-rich melanomas.” Moreover, Dr. Merlino added, inhibiting interferon-gamma immediately after sunburn, an approach that his lab is pursuing, may prove to be an effective preventive strategy against UV radiation-induced melanoma.

Also In the News: Health Disparities Report Shows Colorectal Cancer Screening on the Rise

The CDC recently released the 2011 CDC Health Disparities and Inequalities Report , the first in a series of reports that examine disparities in social and health indicators. The report covers topics ranging from health care access to infant mortality to unhealthy air quality exposure.

One chapter of the report addresses disparities in colorectal cancer screening rates. CDC researchers used data from the Behavioral Risk Factor Surveillance System surveys to look at changes in colorectal cancer screening rates from 2002 to 2008. Overall use of screening tests increased by more than 10 percentage points (from less than 54 percent to more than 64 percent) during that time, the researchers found, but disparities still existed among certain groups. Household income, access to health insurance, and education also influenced these screening rates. For instance, screening increased by only about 4 percentage points among American Indian/Alaska Native populations and by 4.5 percentage points among those without health insurance.

The report states that “differences in health based on race, ethnicity, or economics can be reduced, but will require public awareness and understanding of which groups are most vulnerable, which disparities are most correctable through available interventions, and whether disparities are being resolved over time.”


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