Advances in the clinical management of patients with non-small cell lung cancer (NSCLC) have been slow, and the 5-year survival which is used as a benchmark for putative cure from this disease, is only 14%. Reasons are the relatively low response rate (25-35%) of NSCLC to chemotherapy, increased toxicity of chemotherapy if used in conjunction with surgery or radiation, and limited acceptance of combined modality treatments by patients and physicians. Recent advances in the identification of molecular determinants of poor outcome from NSCLC hold the promise for therapeutic decisions based on individual patient's molecular tumor profiles. We found that allele loss on chromosome segment 11p15.5 is predictive of poor survival in NSCLC patients. We identified a series of genes and putative genes and found that RRM1, a gene in this region, when transfected into human and mouse NSCLC cell lines resulted in a significant reduction of in vitro migration, invasion, and proliferation. In a syngeneic mouse lung cancer model, overexpression of this gene resulted in decreased spontaneous metastasis formation and longer survival. We were able to show that this effect is at least partially mediated through induction of PTEN expression and reduced phosphorylation of focal adhesion kinase (FAK). Further in vitro studies showed that overexpression of RRM1 also resulted in retardation of progression through G2-phase of the cell cycle, increased efficiency of radiation-induced DNA damage repair, and induction of apoptosis. These effects were observed at physiological levels of gene expression. Patients whose NSCLC expressed RRM1 at high levels lived significantly longer than those with low levels of expression, and RRM1 and PTEN expression were highly correlated. Gemcitabine's activity in NSCLC is partially mediated through inhibition of RRM1 function. Preliminary results on a limited set of patients who received gemcitabine showed that response to treatment was associated with RRM1 expression. These data have led us to pose the hypothesis that RRM1 is an important molecular determinant of response to gemcitabine-based chemotherapy and radiation and survival in patients with NSCLC. The purpose of this application is to corroborate this hypothesis in a prospective phase II clinical trial with gemcitabine-based chemotherapy and radiation in patients with locally advanced inoperable stage III NSCLC. ? ?
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