Chong-xian Pan M.D., Ph.D.

Lay Description

Lung cancer is the most common cause of cancer death in America. Bronchioalveolar carcinoma (BAC), a subtype of lung cancer, commonly occurs in middle-age women without a history of tobacco smoking. Although some patients with early disease can be successfully treated with surgery, the long-term prognosis for most is poor. Therefore, effective new approaches to treat this disease are desperately needed.

BAC is a unique type of cancer that grows along the airways of the lung without invading deeper tissues. This study will deliver a form of gene therapy specific for BAC by an inhaled aerosol, a method that will reach the abnormal tissue in high concentrations without affecting the rest of the body.

Adenovirus is a virus that can kill the cells that it infects. The goal of this study is to modify viral DNA to create a virus that can only infect BAC cells. The genetically altered virus is “turned on” to proliferate within (and thereby destroy) the cells it infects only if the host cells have both an enzyme associated with surfactant production (which only airway lining cells have) as well as a BAC tumor specific enzyme. Therefore normal cells not having both enzymes will be spared.

This treatment approach is radically different than other modalities such as radiation therapy, chemotherapy, and surgery. It is delivered to its target by a unique method (aerosol) that takes advantage of the superficial location of BAC cells along the lining of the airways in the lung. The hypotheses of this study will be tested in a mouse model.

Scientific Abstract

Bronchioalveolar carcinoma (BAC) is highly resistant to chemotherapy and radiation therapy. Currently, the only curative therapeutic approach would be surgical resection of early-stage disease. Most patients succumb to BAC even with the treatment of Gefinitib, an inhibitor to the epidermal growth factor receptor tyrosine kinase. Gene therapy has been clinically ineffective in the treatment of cancer because of failure to deliver sufficient amount of virus to tumor cells secondary to poor specificity of infection and development of neutralizing antibody. BAC is an ideal target for gene therapy because of its inability to invade and easy accessibility of viral delivery. Nevertheless, so far, no virus is available that is specific to BAC. Our laboratory has been working on prostate-restricted replicative adenovirus for several years with very promising results. We have identified that the replication and cell eradication of adenovirus can be restricted to certain cells by controlling the expression of the adenoviral early genes with cell-specific promoters. In this study, we plan to incorporate two promoters into the viral genome to restrict the cell killing into BAC cells only. One of these two promoters is specific to cancer, such as hTERT, and the other one is specific to lung tissue. We anticipate that, by controlling the expression of viral early proteins with these two promoters, the replication and cell lysis of adenovirus will be restricted to BAC cells while sparing the surrounding normal lung tissue. An orthotopic preclinical BAC model generated with human BAC cells will be studied because it better reflects the pathophysiology of BAC in vivo.