Lung cancer is the leading cause of death in the United States for both men and women and it is estimated that in 1998, 178,100 new cases of lung cancer will be diagnosed and 160,400 deaths from this cancer will occur. Approximately 80 percent of all lung cancers are non-small cell lung cancers (NSCLC) and these cancers are relatively refractory to chemotherapy. A better understanding of the molecular pathogenesis of NSCLC could lead to better forms of therapy. The epidermal growth factor (EGF) receptor, the ErbB-2/neu/HER-2 receptor and the platelet-derived growth factor (PDGF) receptor are each overexpressed in a substantial number of NSCLCs and these receptors transmit growth-promoting signals to the nucleus via the Ras/mitogen-activated protein (MAP) kinase pathway. The ligands corresponding to these growth factor receptors are produced frequently by NSCLCs or by supporting matrix cells suggesting autocrine or paracrine stimulatory loops of the Ras/MAP kinase pathway. Because of the lack of suitable assays, there have been no measurements of the activation state of Ras or of MAP kinase in NSCLC. However, the principal investigator has recently devised a method that allows one to measure the activation state of Ras in primary human cancers and has successfully applied this method to neurosarcomas, malignant astrocytomas and breast cancers. Of seven NSCLCs analyzed to date, Ras showed increased activation in five, one of which had a genetic mutation in K-ras codon 12 as the explanation for increased Ras activation. In three of the other four tumors with increased Ras activation, the EGF or ErbB-2 receptors were overexpressed suggesting that receptor abnormalities can indeed lead to Ras activation. In this R21 application, they propose to measure the activation state of Ras and of MAP kinase in 80 NSCLCs and 20 normal lung samples over a two year period. All samples will be assessed for K-ras activating mutations and expression of a mutant or wild type EGF receptor, the ErbB-2 receptor and the PDGF receptor; results will be correlated with clinical and histopathological parameters. A large number of Ras inhibitors have been developed by the pharmaceutical industry and several are in phase I Clinical Trials. By assessing the degree of Ras activation in a tumor, one can predict a priori, prior to initiating therapy, whether a patient will be a candidate for a Ras inhibitor when these agents become clinically available. Thus, the proposed work will provide new information about the molecular pathogenesis of NSCLC and may ultimately lead to novel treatments of this cancer. The work is, therefore, responsive to PA-98-022, """"""""Exploratory Studies in Cancer Diagnostics.""""""""
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