NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
September 19, 2006 • Volume 3 / Number 36 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

Autoimmune Disorders Linked to Elevated Risk of Hodgkin Lymphoma

Personal and family histories of autoimmune conditions are associated with an increased risk of Hodgkin lymphoma (HL), according to study results in the September 20 Journal of the National Cancer Institute.

Dr. Ola Landgren of NCI's Division of Cancer Epidemiology and Genetics and colleagues conducted a population-based case control study using data from the Swedish and Danish Cancer Registries, Swedish Multi-Generational Registry, and Danish Central Population Registry. Researchers identified 7,476 case subjects with a first-time HL diagnosis and matched them to 18,573 control subjects by sex, year of birth (within 5 years), and county of residence. More than 86,000 first-degree relatives of case and control subjects also were identified. Subjects were further linked to the Swedish and Danish Inpatient Registries to collect information on discharge diagnoses and 32 autoimmune conditions. All autoimmune conditions were analyzed both individually and by grouping into categories that incorporated knowledge about similar biologic characteristics of autoimmune conditions.

Individuals with a personal history of specific systemic autoimmune conditions - in particular, rheumatoid arthritis and systemic lupus erythematosus - had a significantly increased risk of HL. The associations of both personal and family histories of sarcoidosis with increased risk of HL suggest shared susceptibility that may be important in HL pathogenesis.

These results have implications for future research. According to Dr. Landgren, "This study provides important clues to the role of immune dysregulation and inflammation in the etiology of HL. Future epidemiological and preclinical studies are needed to explain underlying mechanisms of the observed associations. We need to better understand whether they are due to systemic immune stimulation or inflammation, immune-modulating treatments for autoimmune disorders, shared susceptibility, or a combination of these factors."

NCI Study Details Celecoxib's Proteomic Impact

A new study from NCI researchers has unveiled a host of proteins not previously known to be influenced by the COX-2 inhibitor celecoxib, a drug that has shown significant potential as a chemopreventive agent for colorectal cancer. The study was published in the September 12 Cancer Epidemiology, Biomarkers, and Prevention.

Celecoxib's influence on these proteins was not a by-product of its inhibition of the COX-2 enzyme, lead author Dr. Iqbal Ali and colleagues from NCI's Division of Cancer Prevention reported, because the colorectal cancer cell line in which they studied its effects did not express COX-2.

"Many of these potential molecular targets of celecoxib...are of considerable significance in cancer biology, and celecoxib-mediated upregulation or downregulation of these proteins is generally consistent with the relevance of their known cellular functions to the process of carcinogenesis," they wrote.

Proteins that were modulated by celecoxib included those involved in functions such as cell cycle arrest and cell death, DNA synthesis, molecular "chaperoning," glycolysis (converting glucose into energy), and many others.

Using advanced proteomic profiling technologies, the research team conducted the first-ever effort to globally profile the proteins affected by celecoxib in a cancer cell line. Profiling was performed before celecoxib treatment and then afterward, using two doses of celecoxib - one small and one significantly larger. Although celecoxib had different effects depending on the dose administered, at either dose there was approximately 30 percent overlap in the proteins with altered expression.

"Detailed analysis of the functional role of novel candidate molecular targets identified in this study," Dr. Ali and co-authors concluded, "would extend our understanding of the chemopreventive effects of celecoxib" and can help lead to "more effective chemoprevention."

Chemotherapy Fails to Improve Survival in Rectal Cancer

Advanced rectal cancer patients benefit from radiotherapy before surgery to remove their tumors, but there is no clear consensus on whether chemotherapy should be given before or after that surgery. Results from a large European study published in the September 14 New England Journal of Medicine suggest that fluorouracil chemotherapy will reduce local recurrence regardless of when it is given, but does not have an effect on progression-free and overall survival.

Using those who received only preoperative radiotherapy as a standard, the researchers evaluated three different ways to add fluorouracil chemotherapy to the treatment: before surgery, after surgery, or both. They found no statistically significant survival differences among any of these groups, yet "regardless of timing, chemotherapy provides a significant benefit with respect to local control," said the study's lead author, Dr. Jean-François Bosset, from the University of Franche-Comté in Besançon, France, a member of the EORTC (European Organization for Research and Treatment of Cancer) Radiotherapy Group.

The 1,011 patients were followed for a median of 5.4 years; 17.1 percent of those who received radiotherapy alone before their surgery had local recurrence, compared with 8.6 percent who had some form of chemotherapy. Fluorouracil was shown to facilitate surgery by shrinking rectal tumors and reducing pathology, though local recurrence was still significantly reduced even when the drug was given only after surgery.

The results suggest that "future trials should focus on eradicating micrometastases," said Dr. Bosset, because distant recurrence was found to be three times more likely than local recurrence.

Response to Antiangiogenic Drugs for Kidney Cancer Linked to Mutations

Researchers have identified an association between certain mutations in the Von Hippel-Lindau (VHL) gene and the response to drugs that inhibit the growth of tumor blood vessels (angiogenesis) in patients with metastatic clear cell renal cell carcinoma (cRCC), an aggressive form of kidney cancer.

Antiangiogenic therapies are more effective than traditional treatments for some patients with metastatic cRCC, but physicians need ways to identify responders. Mutations in VHL, a tumor-suppressor gene, could potentially be used to help predict response if the association can be confirmed in larger studies.

In this study, the cancer took longer to progress in patients who took antiangiogenic agents such as bevacizumab (Avastin) and had mutations that severely altered the VHL protein. Twenty-five of 43 tumors had a VHL mutation. The median time to disease progression was 13.7 months for patients with mutations that extensively altered the structure of the VHL protein, compared with 7.4 months for patients with less extensive alterations, and 5.5 months for patients with no VHL mutation.

Mutations in the VHL gene are responsible for half of noninherited cases of cRCC. The mutations result in greater expression of the vascular endothelial growth factor (VEGF) and its receptor. VEGF, a regulator of angiogenesis, is a target of drugs such as bevacizumab.

The researchers concluded that the response to therapies targeting the VEGF pathway in patients with metastatic cRCC may be associated with VHL mutations that extensively alter the structure of the VHL protein. The findings were presented by Dr. Erich Jaeger of the University of California, San Francisco, on September 13 at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.