The overall goal of this project is to develop and improve therapeutic and chemoprevention strategies forlung cancer through inhibition of one or more autocrine / paracrine growth factor signal pathways.Autocrine / paracrine growth loops play a major role in the pathogenesis and progression of human lungcancer. Despite proof of concept and exciting preclinical data, only EGFR TKIs are approved for lungcancer therapy and additional prospective studies on the use of biomarkers for selection are needed. Ourprior studies have focused on neuropeptide and EGFR signal pathways. We developed and evaluatedpredictive biomarkers for patient selection for EGFR TKIs showing that EGFR gene copy number by FISHis an excellent predictive marker as are deletions in exon 19 of the EGFR. EGFR protein expression byIHC is not as effective as EGFR gene copy number by FISH but may add value. A predictive proteomicprofile and expression of epithelial markers are also under evaluation. We developed a novel bradykinin 2receptor (BK2R) antagonist, termed CU201, defined its activity in preclinical models, its pharmacokineticprofile in mice and monkeys, and its toxicology in mice and monkeys in preparation for a clinical trial. Wealso demonstrated the importance of FGF loops in lung cancer and showed that FGFR inhibitors inhibit thegrowth of lung cancer cell lines expressing ligand and receptor and synergize with EGFR TKIs in cell linesexpressing TGFa and/or EGFR. Biomarkers for IGFs and IGFRs were also developed. In the upcominggrant cycle we plan to test inhibitors of EGFR,FGFR, IGF-1R and BK2R alone and in combination in apanel of lung cancer cell lines that will be characterized for expression of each ligand and receptor. The celllines will also have their global gene expression determined by Affymetrix arrays to search for othercandidate predictive markers. We believe that the planned preclinical and clinical trials will allow us toidentify and validate biomarkers that will be useful in selection of growth factor inhibitors alone and incombination for lung cancer patients.
Our specific Aims are: 1) Define the role of bradykinin, EGF, FGFs,and IGFs in autocrine / paracrine growth of lung cancer by determining the expression of growth factorreceptors and their ligands on a panel of lung cancer cell lines; determining the sensitivity of these cell linesto growth factor inhibitors and determining the relationship between sensitivity and ligand/receptorexpression. 2) Determine whether expression of growth factor receptors, their ligands and sensitivity toindividual inhibitors predicts combination effects in vitro and in vivo by testing rationally selectedcombinations in defined lung cancer cell lines. 3) Determine if FGFR, IGF-1R, IGF-2R, and BK2Rexpression and activity correlate with prognosis in lung cancer patients by analysis of frequency of receptor/ ligand expression of each receptor and ligand in human lung cancer tissue microarrays. We will alsoexamine the relationship of various receptor / ligand combinations on prognosis, the relationship betweenexpression and other clinical features (gender, smoking status, histology, etc.), and the relationshipbetween signal pathways. 4) Conduct a phase I clinical trial of CU201 in advanced solid tumors withpharmacokinetic and pharmacodyanmic assessments. 5) Evaluate biomarkers selected from our preclinicalstudies for their utility in patient selection for clinical trials of EGFR, FGFR, BK2R, and IGF-1R inhibitors,alone and in combination.
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