The Intervention Section studies aspects of the biology of cancer to devise effective strategies for cancer mortality reduction. Lung cancer is the most lethal cancer and has been a logical focus for this research. Based on early success with detecting lung cancer with sputum diagnostic, the need for and the conceptual appeal of developing managements for early lung cancer emerged as an important research opportunity. Significant improvements in standard diagnostic imaging using helical computerized tomography (CT) has outstripped progress with all other lung cancer detection technologies and provides a near-term tool for routine detection of early (pre metastatic) cancer. However, there has been considerable disruption inherent in the rapid transition with the size of an early lung cancer detected by chest X-ray being about 3cm to the current situation with under 8mm lung cancers being detected using spiral CT at some centers during annual screening. Conducting research to improve the safety and efficiency of clinical management for these very small cancers could be a profound contribution to public health and mirrors parallel opportunities in other organ sites. One major effort is to develop appealing lead compounds for use in the pharmacological management of early lung cancer. It is arguable that drug side effects have been as significant a problem as lack of drug efficacy in lung cancer chemoprevention research. We have focused on a few promising opportunities to evaluate the issue of optimal drug dosage. In our laboratory work, we have identified the lipoxygenase inhibitor, MK886 as a particularly interesting candidate for chemoprevention evaluation. We have studied aspects of drug exposure with this agent to determine the critical requirements for therapeutic success. To further improve therapeutic index, we have looked at the interaction of rational drug combinations to determine if we could further reduce the administered dose of particular agents and increase the overall safety factor. In the course of this translational work, we have found interesting mechanistic leads. For reasons of safety as well as cost, we have a long standing interest in developing aerosolized drugs for local/regional lung cancer therapy. A simple demonstration of utility in this regard involves the use of an IND-approved, nanoformulated iodine contrast material agent as an aerosol to enhance the sensitivity of respiratory mucosal and nodal imaging with spiral CT. If these applications are successful, we could also co-formulate nanoparticulate iodine with new candidate drugs that we are evaluating for local delivery to treat airway confined early lung cancer. These nanoconjugates provide a simple way to define the distribution and clearance from the airway of aerosolized drugs. This is a very simple project in which early feedback should be readily available. Developing less toxic targeted drug delivery approaches for early cancer management may be a valuable contribution from the intramural program. In a related project, we have studies the utility of non steroidal anti inflammatory drugs. Ketoprofen has been formulated as a nanoparticle under a Material Transfer Agreement with ELAN but it failed to inhibit angiogenesis in a chick aortic ring assay. In that same set of experiments, indomethacin was potent in reducing angiogenesis. We are now reformulating that drug with ELAN to evaluate if this drug formulated as a nanoparticle blocks cyclooxygenase activity in vitro, inhibits chick aorta angiogenesis and then determine the utility of these agents in an NNK/BaP AJ models. A goal is to bring interesting compounds into Phase I/II trial to evaluate novel approaches. After promising pre clinical work under a Clinical Trials agreement with Procter and Gamble, we have published a trial evaluating local delivery as an approach to reduce significant systemic drug side effects using an oral formulation of another non steroidal drug in a precancerous condition of the oral cavity, leukoplakia. As we outlined in the report, drug percolation may have been an important but unrecognized issue. Extrapolating from a published experience in skin cancer, it is likely that the oral rinse formulation of ketorolac did not penetrate the keratin layer of the mucosa, where it could effect prostaglandin production of the evolving cancer cells. Therefore, we are working to reformulate this drug to evaluate partitioning of this agent in a rodent model. This is a project to develop new agents for administration in the pre invasive stage of lung cancer. Vitamin A analogues have the greatest reported activity of any of the agent used in chemoprevention of tobacco-related malignancies. The relationship between the administered dose and the resulting in vivo dose at the site of the target organ is poorly understood. We propose to change the route of administration of the retinoid to improve the therapeutic index. This work has been supported by preclinical toxicology studies conducted under a NIH CRADA with Battelle Labs. The amount of drug required to saturate the bronchial epithelium when delivered as an aerosol is significantly lower than the systemic dose required to deliver a comparable amount of drug to the target organ. Early lung cancer exists only in the tracheobronchial tree where the effects of chronic cigarette smoke have caused diffuse cancerous injury. The beneficial effect of retinoids on cancer cell growth is a direct drug/cancer cell interaction. If the airway is effective as a conduit for the carcinogen, it may also be the most effective way of directing retinoids to the affected early lung cancer cells. Aerosolizing retinoids into the airway instead of giving them orally can result in better bioactivity of the chemoprevention agent while potentially causing less frequent systemic side effects since the blood levels after an aerosolized dose will be much lower. We are proceeding to conduct an initial Phase I/II trial of aerosolized retinoids at the Clinical Center. Two papers outlining the success of this effort in tobacco-carcinogen induced lung cancer models in rodents have been published. Due to the substantial progress on this effort, we will be able to start a clinical trial in late 2000. A range of other active cytotoxic agents will also be evaluated to determine if limited intrapulmonary drug exposure is sufficient to control early, small volume lung cancer. A Phase I trial with aerosolized doxirubicin is ongoing which represents a first step in this regard. With recent developments with spiral CT, routine detection of such small primary lesions is expected and this may drive the need for effective aerosolized chemotherapeutic drugs. The preclinical rationale for this approach has been bolstered by a large in vivo experiment with carcinogen-induced lung tumors. In a series of exposures through a range of retinoid doses, a clear dose response emerges as to the success of retinoid to suppress the frequency of lung tumors developing.We recently completed a Phase II clinical trial which evaluated the efficacy of a locally administered pan cyclooxygenase inhibitor in a randomized trial of individuals with oral leukoplakia. The report has been accepted for publication in the journal Clinical Cancer Research. The cyclooxygenase inhibitor was well tolerated but did not lead to enhances drug response when compared to placebo control. As discussed in the report, this experience has given us important feedback to consider in the development of subsequent drug delivery efforts for early epithelial cancer.A challenge with this approach is that the pharmaceutical industry does not anticipate that a large enough target population will exist to justify the requisite investment to develop these drugs.
