Celecoxib Effective in Inhibiting Genetic Basal Cell Carcinoma

Roxanne Nelson

January 07, 2010

January 7, 2010 — A new study adds to the growing body of evidence suggesting that nonsteroidal anti-inflammatory drugs (NSAIDs) exert a chemopreventive effect. Although much of this research has been directed toward colorectal cancer, new findings show that NSAIDs might help protect against basal cell carcinoma.

The results of the trial, published in the January issue of Cancer Prevention Research, found that the cyclooxygenase (COX)-2 inhibitor celecoxib (Celebrex) significantly decreased the development of basal cell carcinomas in people with a rare disorder that genetically predisposes them to the disease.

In patients with fewer than 15 active lesions at baseline, those who received placebo had a 50% increase in basal cell carcinoma burden per year; those who received celecoxib had a 20% increase. Among patients with more severe disease (more than 15 active lesions at baseline), a trend was observed for celecoxib reducing the disease burden.

"This new study of cyclooxygenase inhibition, together with recent data on the efficacy of hedgehog pathway inhibition, offers new hope for patients at a high risk for basal cell cancer," notes Charles M. Rudin, MD, PhD, in an accompanying editorial.

The prostaglandin metabolic pathways regulated by the COX-1 and COX-2 enzymes have been implicated in many carcinogenesis models, explains Dr. Rudin, associate director for clinical research at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, in Baltimore, Maryland. This includes the development of squamous cell carcinoma, a less commonly occurring type of nonmelanoma skin cancer.

The current study "highlights the power of studying rare and highly disease-prone patient populations," he writes. "Clinical trials of chemopreventive strategies in patients with rare genetic syndromes are feasible in the internet age, provide important biological insights, and have implications for cancer prevention in more broadly defined populations of lesser-risk individuals."

Efficacy First in Mice

In this study, a team led by Jean Y. Tang, MD, PhD, assistant professor of dermatology at Stanford University in California, evaluated the effectiveness of celecoxib in preventing basal cell carcinoma carcinogenesis in patients with basal cell nevus syndrome, also known as Gorlin syndrome. People with this syndrome are genetically prone to developing numerous basal cell carcinomas, which can number in the hundreds or even thousands.

The authors note that studying chemoprevention in this population mirrors the testing of colorectal cancer chemopreventive agents in patients with familial adenomatous polyposis coli prior to conducting longer and more expensive trials in those with sporadic colorectal adenomas.

However, they point out that their analysis is different from other chemoprevention studies, in that it is "possible to assess directly the numbers and growth of the actual cancers that are the prevention targets, not simply the numbers of precancerous lesions or surrogate end points."

Basal cell nevus syndrome patients carry germ-line heterozygous mutations in PTCH1, which encodes a primary inhibitor of hedgehog signaling. All sporadic and familial basal cell carcinomas have aberrant hedgehog signaling caused by mutations, say the authors.

The authors first evaluated the relative importance of the COX enzymes in basal cell carcinogenesis, and quantitated basal cell carcinomas in Ptch1 +/− mice lacking or overexpressing COX-1 or COX-2. Next, they assessed the results of inhibiting COX with celecoxib to prevent basal cell carcinoma in Ptch1 +/− mice.

They found that carcinogenesis in Ptch1 +/− mice correlated with COX enzyme expression, and that genetic deletion of COX-1 or COX-2 decreased the microscopic tumor burden by 75% (P < .05). However, pharmacologic inhibition with celecoxib was less effective in reducing the microscopic basal cell carcinomas (35%; P < .05).

Preventive Effects Significant in Patients With Less Severe Disease

On the basis of these findings, they proceeded to the next phase, in which 60 patients with basal cell nevus syndrome were randomized to receive oral celecoxib 200 mg twice a day or placebo.

Total skin examinations were conducted every 3 months, and patients continued to receive care from their own physicians, who removed visible lesions using whatever modality they decided would be the most clinically appropriate.

In the third year of the study, the authors discontinued the use of celecoxib because of emerging evidence of an association between COX-2 inhibitors and increased risk for cardiovascular events. However, they continued to observe all patients for basal cell carcinomas.

When lesions were assessed by number or burden at the end of the 36-month trial, patients who received placebo had a 37% increase in basal cell carcinomas per year (< .001). This was compared with a 26% increase among patients who received celecoxib (P < .001), but the difference in the percent change was nonsignificant.

The patients were also stratified by the number of basal cell carcinomas at baseline (15 or more or less than 15). Celecoxib use reduced the change in the number of lesions in patients with less than 15 at baseline, but did not have an effect on those with 15 or more lesions (48% vs 22%; P = .043).

None of the participants experienced a serious adverse event or a laboratory-detected abnormality related to the study drug, the authors note; specifically, there were no myocardial infarctions or cerebrovascular accidents.

New Possibilities Need Investigation

In a second editorial that appears in the same issue of the journal, Jack L. Arbiser, MD, PhD, asks what the fastest way is to translate these findings to the clinic.

Dr. Arbiser, a professor of dermatology at Emory University School of Medicine, in Atlanta, Georgia, points out that the heightened risk for cardiovascular events in patients taking COX inhibitors "makes us cautious about recommending the widespread use of these drugs for patients at a high risk of basal cell carcinoma."

However, the studies should lead researchers to consider and investigate other possibilities, he writes, including the fact that small molecules derived from plants have been shown to inhibit COX without causing cardiac toxicities.

A combination approach might be warranted, such as drug combinations that target COX-src activation and sonic hedgehog signaling, and "combinations that may be synergistic in decreasing the burden of [basal cell carcinoma] in patients with or at a high risk of this disease," he concludes.

The study was supported by grants from the National Institutes of Health and Office of the Director University of California at San Francisco–Clinical and Translational Science Institute, and by the Mike Rainen Family Foundation, Patricia Hughes, and Stanley Eisenberg. The study authors have disclosed no relevant financial relationships. Dr. Rudin reports receiving research support on the hedgehog pathway from the Burroughs Wellcome Fund, but has disclosed no relevant financial relationships. Dr. Arbiser reports receiving grant support from a Veterans Administration Merit Award, the National Institutes of Health, the Jamie Rabinowitch-Davis Foundation, and the Minsk Foundation; and pursuing patents on honokiol and Tris (dibenzylideneacetone) palladium.

Cancer Prev Res. 2010;3: 1-3, 4-7, 25-34. Abstract, Abstract, Abstract

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