PDGF as a Gene Therapy Target in Lung Cancer

The platelet-derived growth factor (pDGF) polypeptides are potent mitogens for connective tissue cells, and their roles in promoting cellular growth and malignant progression have been firmly established for such human cancers as glioblastoma and osteosarcoma. However, the role of PDGF has not been studied as extensively in lung cancer, despite reports of PDGF overexpression in all forms of this disease. Overproduction of PDGF by the primary lung carcinoma cell is almost certainly a key factor in various aspects of tumor stromal development (paracrine growth stimulation), while additional evidence has been put forth to suggest that PDGF autocrine growth loops may also be operative. Our previous research on PDGF has indicated two promising avenues for gene therapy of lung cancer. First, we have developed dominant-negative forms of PDGF that reverse the transformed phenotype in human glioblastoma cells. In this proposal, .we will measure the extent to which these (and other mutant proteins designed to disrupt PDGF-stimulated growth) can block the malignant growth of human lung carcinoma cells, both in cell culture and in vivo model systems. Second, we have recently identified a DNA enhancer element (ACE66) in the far upstream region of the PDGF-A gene that is highly activated in many human tumor cell lines. In this proposal, we will employ the ACE66 element to drive expression of the "suicide gene" encoding thymidine kinase and will measure its efficacy for killing of lung carcinoma cells in cell culture and in vivo model systems. Recent studies in our laboratory have demonstrated that three tandem copies of the ACE element confer over 30-fold enhancement of transcription in the non-small cell lung carcinoma cell line, A549. Considering the current paucity of transcriptional elements available for directing lung cancerspecific, high-level expression of suicide genes, the proposed studies appear to hold considerable promise for this approach to lung cancer treatment. Overall, the proposed studies should also advance our current knowledge about the specific role played by PDGF in lung cancer development and progression.