New Targets for Aerodigestive Cancer Prevention: Where Do We Go from Here?
Eva Szabo, MD
Chief, Lung and Upper Aerodigestive Cancer Research Group
Division of Cancer Prevention
National Cancer Institute
National Institutes of Health
While substantial preclinical and epidemiological data indicate that cancer is preventable (at least in part), the dilemma facing the scientific community today is how to efficiently identify strategies that can be delivered to large at-risk populations. A rapidly expanding understanding of the biology of aerodigestive carcinogenesis provides many potential targets for intervention, but enthusiasm for any given intervention needs to be balanced with the risks and toxicities associated with such a strategy. The following review will outline the issues that need to be considered prior to embarking on clinical trials and will discuss some of the new targets currently being investigated in aerodigestive cancer prevention clinical trials.
Considerations for Target Selection
There are multiple considerations to take into account when identifying promising cancer prevention strategies, ranging from the efficacy and toxicity of the intervention to the size of the target population and the economic as well as psychological costs of delivering interventions to large populations. The development of epithelial cancers is a lengthy process requiring years of exposure to carcinogens. The efficacy of medical interventions is decreased in late disease in comparison to early disease as evidenced by the improved efficacy of chemotherapy regimens in adjuvant versus metastatic settings in cancers originating in the breast, colon, and, as demonstrated more recently, lung. Thus, early intervention during carcinogenesis prior to the development of invasive disease is appealing. However, the size of the at-risk population is much greater in the early phases of carcinogenesis than in advanced disease. In the US in 2003, there were 91.5 million current and former smokers, in comparison to 172, 000 new cases of lung cancer. Thus, the potential gains in the ability to intervene at early stages need to be balanced against the increased numbers of people who would need to be treated. Included in the calculation would be the economic costs not only of the actual interventions, but also the associated health care costs required for their delivery and for treating the resulting side effects.
Although risk-benefit calculations apply to all medical interventions, maintaining the balance is particularly challenging in a population that is at risk for life-threatening disease but is otherwise asymptomatic. The toxicity profile of the intervention agent must be benign both to justify long-term treatment from a global public health perspective and to obtain sufficient compliance for effectiveness. Since almost all interventions, including ones based on dietary constituents, are likely to have some side effects, it is critical to identify the most appropriate high-risk cohorts who stand to gain the most from interventions. The higher the risk of the cohort to be treated, the greater is the toxicity of the potential intervention that can be tolerated. For instance, there is considerable heterogeneity in the progression rate to cancer in oral leukoplakia, a precursor to oral cancer. Among dysplastic oral leukoplakias, however, the majority of cancers develop from aneuploid lesions, while diploid lesions rarely progress to overt carcinoma. Since these cancers develop fairly quickly, interventions associated with greater toxicities would be acceptable for this very high-risk population. There is a great scientific need to develop improved risk assessment tools to identify the truly high-risk individuals from among all current and former smokers who are most likely to benefit from interventions. Similarly, treatment strategies that minimize toxicity, such as regional drug delivery (e.g., inhalation or oral mouthwash), may be instrumental in shifting the risk-benefit balance in the right direction.
Substantial data have accrued in recent years suggesting that inflammation plays a crucial role in the genesis of lung cancer and that various anti-inflammatory compounds can prevent cancer development. Wattenberg and others have demonstrated that both systemic and inhaled steroids, which inhibit the generation of arachidonic acid from membrane phospholipids by phospholipase A2, can inhibit the development of lung adenomas and carcinomas in mice treated with a variety of carcinogens. Based on this rationale, Lam et al conducted a phase IIb randomized, placebo-controlled trial of inhaled budesonide in persons with bronchial dysplasia. Participants were selected on the basis of central airway pathology (bronchial dysplasia) but underwent monitoring of both their central and peripheral lung via autofluorescence bronchoscopy and spiral CT. Although the six-month treatment did not result in regression of the central airway dysplasias (the primary study endpoint), there was an increased rate of resolution of CT-detected peripheral nodules (a secondary endpoint). Since the animal models correspond to events occurring in the peripheral lung, these human and animal data provide the rationale for a new trial currently in development that uses inhaled budesonide in high-risk smokers with spiral CT-detected persistent nodules that are more likely to represent precursor lesions for lung adenocarcinomas.
Similar animal data showing inhibition of carcinogen-induced lung tumorigenesis exist for inhibitors of formation of products of arachidonic acid metabolism by the enzymes 5-lipoxygenase (5-LO) and cyclooxygenase (both the COX-1 and COX-2 isoforms). Inhibitors of these enzymes, zileuton (5-LO), celecoxib (COX-2), and sulindac (COX-1 and COX-2), are currently under study for either prevention of lung or oral cancer in multiple phase IIb studies with endpoints ranging from effects on proliferative indices to effects on intraepithelial neoplasia (bronchial dysplasia or oral leukoplakia). In addition, studies of combinations of celecoxib and epidermal growth factor receptor (EGFR) inhibitors are also underway in lung and oral preneoplasia based on a strong preclinical rationale demonstrating a positive feedback loop between EGFR and COX-2 signaling, with extra benefit to be obtained with simultaneous targeting of both.
Another target for aerodigestive cancer prevention is the peroxisome proliferator-activated receptor gamma (PPAR gamma), which is a ligand-activated nuclear transcription factor belonging to the steroid receptor superfamily and the target for the thiazolidinedione class of antidiabetic drugs that are currently being used for type II diabetes mellitus (pioglitazone and rosiglitazone). Cell line data show that PPAR gamma ligands induce growth arrest, differentiation, and apoptosis in a variety of cancer cell lines, while animal carcinogenesis studies show a potent cancer preventive effect in an oral cancer model system. A clinical trial testing the effectiveness of PPAR gamma ligands in oral leukoplakia is currently underway.
A greater understanding of the molecular events responsible for the development of cancer and the availability of a wide array of new molecularly targeted agents offer many possibilities for interfering with the progression of aerodigestive cancers. Translation of these biologic findings to clinical trials and eventually to population-based delivery requires a careful assessment of the risks and benefits of each strategy and identification of the appropriate target cohorts. Understanding the clinical context for cancer prevention in terms of long-range treatment of large asymptomatic populations is necessary for the appropriate selection of therapeutic targets for further development. The partnership between clinician, basic scientist, pharmaceutical company, and regulatory agencies lies at the core of further progress.