Former Smokers Benefit from ‘Re-tooled’ Chemoprotective Agent

SAN FRANCISCO—A drug used to treat xerostomia in Sjögren's syndrome and other diseases is also effective in preventing lung cancer in smokers or former smokers, according to results of a Phase II study from Canada presented at the American Association for Cancer Research Annual Meeting here. Data on the chemopreventive agent show that it prevented or slowed the development of lung dysplasias most effectively in people who had already quit smoking. The study was highlighted in an AACR news conference as one of several noteworthy “late-breaking” research studies. Another report discussed at the news conference described a new compound that acts on the mTOR protein, and appears to inhibit tumor cell growth by making the cells act as if they were in a starvation environment. Dry Mouth Drug ADT (anethole dithiolethlone) is marketed under the trade name Sialor in Canada and Sulfarlem in Europe for treatment of xerostomia. Canadian researchers have found that it is also a potential chemoprevention agent for lung cancer, with therapeutic effects based on ADT's radical scavenger and glutathione-inducer properties. It is not currently approved in the U.S. The study's principal investigator said ADT could help in preventing lung cancer in long-time smokers who are tying to quit. “While it is widely known that tobacco smoking is a major cause of lung cancer, it is not so widely known that people who quit after a long time as smokers retain a substantial risk of lung cancer,” said Stephen Lam, MD, Chair of the Lung Tumor Section at the British Columbia Cancer Agency in Vancouver. Fifty percent of newly diagnosed lung cancer patients are former smokers, Dr. Lam noted. “ADT can prevent or halt the development of lung cancer as well as the appearance of new pre-cancer lesions in the bronchial tubes.” Dr. Lam's placebo-controlled Phase IIb clinical trial included 101 current and former smokers above age 40 who had smoked more than a pack of cigarettes a day for 30 years or more. They were randomly assigned to receive either ADT at 25 mg three times a day or placebo, for six months. All patients began the study with bronchial dysplasia identified by autofluorescence bronchoscopy, which Dr. Lam said have a high risk for progression to invasive cancer. At the end of the six-month study the precancerous areas were biopsied, as were any new lesions that had appeared. When all lesions in the study were analyzed, the progression of preexisting dysplastic lesions and the appearance of new lesions was 9% lower in the ADT group, he reported. When lesions were analyzed per person, the progression rate was 22 percent lower, Dr. Lam said. The person-specific results are more significant for treatment, because individuals can be more sensitive or more resistant to different agents. About two thirds of subjects were smokers and one third, former smokers, and the data showed that ADT had more effect in those who had already quit. The treatment was safe with only mild abdominal bloating or flatulence that could be treated by dose reduction or discontinuation of the medication, Dr. Lam said. “But the effect seems to be maintained even in people taking the reduced dose.” mTOR & Starvation Mode In the second late-breaking abstract featured at the news conference, researchers said the rapamycin nonprodrug-analog AP23573 appears to inhibit a relatively new emerging target called mTOR in animal cancer models. AP23573 compound is a natural product made by bacteria, said Tim Clackson, PhD, Vice President for Gene Therapy and Genomics at ARIAD Pharmaceuticals in Cambridge, MA, which is developing the drug. He said mTOR is an ATM-family kinase that links mitogenic stimuli and nutrient status to cell cycle progression. Inhibition of mTOR induces a dramatic metabolic arrest that mimics the cellular response to starvation. “AP23573, by blocking the action of mTOR, prevents cells from getting signals that tell them that nutrients such as carbon and nitrogen are available,” Dr. Clackson said. Rapamycin is currently used to suppress the immune system during organ transplantation, which it does by blocking mTOR. But AP23573, unlike rapamycin, can be given intravenously or orally. “Compounds that inhibit mTOR work through a relatively newly recognized mechanism that I'll call tumor starvation,” Dr. Clackson said. “AP23573 works by fooling tumor cells into thinking that they are in a starving environment that lacks nutrients, causing the tumor cells to shut down even in the face of plentiful nutrients.” He said AP23573 was developed using structure-based drug design, a technique that exploits knowledge of the atomic mechanism by which a drug binds to its target. Dr. Clackson said AP23573 is a potent inhibitor in particular of cell lines that lack the tumor suppressor gene PTEN. Recent studies show that the Akt/PTEN/mTOR pathway is mutated in many human cancers, and that PTEN-deficient tumors are hypersensitive to mTOR inhibition. In the research described at the AACR meeting, Dr. Clackson and colleagues grafted human glioblastoma cells into mice with a defective immune system that does not reject human cells as foreign. They then treated the mice with low-dose injections of AP23573 for five days, followed by nine days off and another five days of treatment. Tumor volume in the treated mice decreased 46 percent compared with 150 percent in untreated mice. Similar tumor shrinkage was seen in mice treated with AP23573 orally on the same regimen, as well as in mice that received weekly injections of the compound. The researchers found that by giving intermittent rather than continuous doses of the compound they could halt tumor growth while avoiding immunosuppression. “The compound is effective in mouse models when injected or when administered orally at fairly low doses, and that suggests we will be able to get treatment that evades mainstream toxicity,” Dr. Clackson said. He added that ARIAD plans to begin clinical trials of AP23573 later this year. Ends of the Spectrum The moderator of the news briefing, Frank J. Rauscher, III, PhD, Professor and Chair of the Molecular Genetics Program at the Wistar Institute in Philadelphia and Editor-in-Chief of Cancer Research, said the two compounds come from two different ends of the development spectrum—one a newly designed molecule and the other a new application for an existing drug. “ADT has already been approved for another indication, but it is also a very potent chemopreventive,” he said “This shows how scientists can essentially re-tool an existing drug.” The implications for ADT in chemoprevention of lung cancer are dramatic, Dr. Rauscher noted. “Preneoplastic lesions in bronchial dysplasia are going to be a huge problem. With 25 percent of the population still smoking, application of a drug like this can have dramatic effects.” AP23573 is in a much earlier time frame, having only completed animal testing. Dr. Rauscher noted that the original research on rapamycin and mTOR was done in yeast. That led to studies that found identical pathways in invertebrates, which are about 600 million years apart in evolutionary time. “After defining the pathway and the genetics, the information was applied through structural-based genomics, using a protein that nature gave us to model a new drug that has much better pharmacological properties,” Dr. Rauscher said. “This is one of the better examples of what we will be seeing as information from the human genome sequence comes online.” Redesigned NCCS Web Site at www.canceradvocacy.org The National Coalition for Cancer Survivorship (NCCS), which launched one of the first patient-focused Web sites in 1995, has redesigned its award-winning original site and changed its address as well. The new site augments the original guide to online resources for newly diagnosed cancer patients with the addition of a comprehensive guide to cancer-specific organizations. Information on such topics as employment, insurance, and clinical trials is also provided. New additions covering cover pain, palliative cancer care, and end-of-life issues are planned. “For 15 years, NCCS has been at the forefront of patient-led advocacy on behalf of people with all types of cancer and their families,” said NCCS President Ellen Stovall, a member of OT's Editorial Board. “Our new Web address better describes our core business—assuring quality cancer care through advocacy and education.” The new address is www.canceradvocacy.org.

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