- Assess the therapeutic potential of semaphorin-3F in lung cancer
- Determine ZEB-mediated alterations in lung cancers
- Determine the role of BKB2R and its signal pathway in lung cancer pathogenesis:
Define specific FGFs and FGFRs as components of novel autocrine signaling pathways in both NSCLC and SCLC that can be targeted with emerging FGFR inhibitors:
- Define the mechanism of action of CU201 and the role of BKB2R in CU201 efficacy
- Explore combination interaction of CU201 with EGFR, FGFR and Src inhibitors;
- Determine the frequency and prognostic relevance of BKR expression in lung cancer TMA’s and in preneoplastic tissues with varying degrees of dysplasia;
- Conduct a Phase 1 trial of CU201 in advanced solid tumors with pharmacokinetic and pharmacodynamic properties. Evaluate biomarkers in the trial.
Define the relationship between autocrine/paracrine signaling pathways to help predict which tumors can be treated successfully with EGFR, FGFR, BKB2R and other growth factor inhibitors alone and in combination.
- Determine if there is a correlation between FGF2, FGF9, FGFR1c, FGFR2c protein and gene expression in lung cancer cell lines and sensitivity to FGFR inhibitors in vitro and in vivo.
- Test for additive/synergistic drug combination interactions in rationally designed combinations of FGFR inhibitors with other targeted agents;
- Determine the prognostic relevance of FGF2, FGF9, FGFR1 and FGFR2 expression in lung cancer TMAs and preneoplastic biopsies.
- Aim 1 examines the effects of iloprost and TZDs on growth, differentiation, and invasiveness in a panel of human NSCLC cell lines. Effects of combinations of inhibitory agents are being examined. Co-culture experiments using NSCLC cell lines determine how NSCLC modulate growth, migration and gene expression of human fibroblasts and microvascular endothelial cells.
- Aim 2 examines the role of PGI2 and PPARg in vivo. The temporal role of iloprost and rosiglitazone in inhibiting lung tumorigenesis in mice are determined using two carcinogenesis protocols. The role of Fzd9 in mediating the effects of Iloprost on NSCLC are tested in vivo using xenograft experiments with cells either expressing or lacking Fzd9.
- Aim 3 defines markers in the PGI2/PPARg pathway using samples of human lung tumors and from chemoprevention trials. Expression profiling of endobronchial biopsies will be performed to define markers of disease severity, and susceptibility/response. Markers associated with severity of dysplasia and smoking status will be defined. Using biopsies from the Iloprost chemoprevention trial, markers associated with response to Iloprost will be defined. Expression of Wnt7a, Fzd9, PPARg, and downstream effectors will be examined in human lung tumors using tissue microarrays, and correlated with clinical parameters.
- Identify and validate candidate biomarkers in sputum that may be useful for population screening and clinical decision making.
- Assess biomarkers of lung cancer risk in tissue, bronchoalveolar lavage and blood. Evaluate these as intermediate endpoints in chemoprevention trials.