The overall goal of this project is to develop and improve therapeutic and chemoprevention strategies for lung 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 lung cancer. Despite proof of concept and exciting preclinical data, only EGFR TKIs are approved for lung cancer therapy and additional prospective studies on the use of biomarkers for selection are needed. Our prior studies have focused on neuropeptide and EGFR signal pathways. We developed and evaluated predictive biomarkers for patient selection for EGFR TKIs showing that EGFR gene copy number by FISH is an excellent predictive marker as are deletions in exon 19 of the EGFR. EGFR protein expression by IHC is not as effective as EGFR gene copy number by FISH but may add value. A predictive proteomic profile and expression of epithelial markers are also under evaluation. We developed a novel bradykinin 2 receptor (BK2R) antagonist, termed CU201, defined its activity in preclinical models, its pharmacokinetic profile in mice and monkeys, and its toxicology in mice and monkeys in preparation for a clinical trial. We also demonstrated the importance of FGF loops in lung cancer and showed that FGFR inhibitors inhibit the growth of lung cancer cell lines expressing ligand and receptor and synergize with EGFR TKIs in cell lines expressing TGFa and/or EGFR. Biomarkers for IGFs and IGFRs were also developed. In the upcoming grant cycle we plan to test inhibitors of EGFR,FGFR, IGF-1R and BK2R alone and in combination in a panel of lung cancer cell lines that will be characterized for expression of each ligand and receptor. The cell lines will also have their global gene expression determined by Affymetrix arrays to search for other candidate predictive markers. We believe that the planned preclinical and clinical trials will allow us to identify and validate biomarkers that will be useful in selection of growth factor inhibitors alone and in combination 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 factor receptors and their ligands on a panel of lung cancer cell lines;determining the sensitivity of these cell lines to growth factor inhibitors and determining the relationship between sensitivity and ligand/receptor expression. 2) Determine whether expression of growth factor receptors, their ligands and sensitivity to individual inhibitors predicts combination effects in vitro and in vivo by testing rationally selected combinations in defined lung cancer cell lines. 3) Determine if FGFR, IGF-1R, IGF-2R, and BK2R expression 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 also examine the relationship of various receptor / ligand combinations on prognosis, the relationship between expression and other clinical features (gender, smoking status, histology, etc.), and the relationship between signal pathways. 4) Conduct a phase I clinical trial of CU201 in advanced solid tumors with pharmacokinetic and pharmacodyanmic assessments. 5) Evaluate biomarkers selected from our preclinical studies 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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