Norwegian study demonstrates targeted coxibs may prevent oral cancer

They will use COX-2 inhibitors (coxibs) – a particular type of non-steroidal anti-inflammatory group of drugs (NSAID) – better known as a treatment for conditions such as arthritis. These drugs block the action of COX-2 (cyclooxygenase-2), an enzyme found mainly in inflammatory and immune cells and now suspected of playing a role in cell growth and genetic instability.

Dr Jon Sudbø, Consultant at the Department of Oncology at the Norwegian Radium Hospital in Oslo, revealed plans for the trial at a news briefing today (Thursday 21 November) at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics[1], in Frankfurt, Germany.

His team at the Norwegian Radium Hospital and colleagues from the University of Oslo Department of Oral Biology, have carried out a study to compare levels of COX-2 expression in three groups of people – 30 with healthy mucous membranes in their mouths, 22 with dysplastic (premalignant) lesions and 29 with oral cancer. The objective was to see whether the levels of COX-2 were linked to aneuploidy (aberrant numbers of chromosomes) in the DNA, indicating a genetic risk marker for cancer. The results are being presented for the first time at the Frankfurt conference.

"We found that COX-2 expression was up regulated from healthy to premalignant lesions and to cancerous oral mucosa," said Dr Sudbø. "There was COX-2 expression in one healthy patient (3%) but all the healthy group had normal DNA. Among those with cancer 26 (88%) had COX-2 expression and 25 (94%) had aneuploidy. But, most notably, we found that of the 22 patients with dysplastic lesions, COX-2 was exclusively expressed in a subgroup of nine (41%) who we identified at high risk of cancer by the aberrant DNA in their lesion. Of these nine patients, we followed seven for at least five years and six of those (85%) went on to develop oral cancer.

"This is the first time that it's been demonstrated that COX-2 is up-regulated in high-risk oral lesions. So, this is also the first demonstration that it may be possible to use targeted coxibs to prevent oral cancer."

Dr Sudbo said that oral cancer was ideal for investigating chemoprevention because it was normally preceded by readily detectable lesions that can be identified and monitored without very sophisticated equipment or procedures.

"Typically, there is a lead-in time of five to 10 years between the occurrence of dysplasia and the development of cancer, so there is ample time to intervene with preventive treatment.

"Quite frankly we regard both the study and the forthcoming trial as a significant development, whatever the results turn out to be. With few and notable exceptions, treating manifest cancers is not an optimal approach to this group of diseases. Treating precursor lesions is a much more attractive approach, mainly because the complexity of the disease in early stages is not as pronounced as in more advanced stages."

He said that most approaches to chemoprevention have failed and this was probably because reliable identification of high-risk individuals had not been possible. The Norwegian Cancer Society had therefore up to now had a "wait and see" approach to chemoprevention.

"Now we have identified risk markers this has changed, at least for oral cancer. The Norwegian Cancer Society is funding the trial with the Norwegian Radium Hospital as the primary investigating site. Our randomised trial, using celecoxib, will involve patients with aneuploid white patches in their oral mucosa. Our target is to recruit 350 patients and we expect the trial to last five years and to follow our patients for 10 years."

Dr Sudbø said that head and neck cancers shared common risk factors with lung cancers. "An interesting spin-off will be to see whether the use of coxibs for preventing oral cancer will also influence the incidence rates of lung cancer. Selective coxibs have already been shown to influence the role of colon polyps," he added.

Notes:

[1] EORTC [European Organisation for Research and Treatment of Cancer; NCI [National Cancer Institute]; AACR [American Association for Cancer Research].