Fibroblast Growth Factor Inhibitors

Abstract

Dr. Ignatio Witsuba (MD Anderson) started this session by giving an overview of the fibroblast growth factor (FGF) pathway and expression of FGFs (22 members), FGF receptors (FGFRs, four members), and their gene family members in non-small cell lung cancer (NSCLC). FGF-FGFR interaction plays crucial role in normal development, and deregulation of their signaling is associated with carcinogenesis. Overexpression of FGFRs (1 and 2) and FGFs (e.g., 2, 7, and 9) has been reported in 50 to 80% of squamous cell carcinoma and adenocarcinoma. Mutations and amplification of FGFR-1, −2, and −4 have also been noted in NSCLC. Moreover, isoforms arising from alternative splicing of these FGFRs may be differentially expressed in various subtypes of NSCLC. Dr. Paul Bunn (Colorado) followed by discussing the novel hypothesis that expression of FGFR 2 and 3 may be transcriptionally activated when NSCLC cells are treated by epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), leading to activation of EGFR downstream signaling (ERK) and possibly resistance to EGFR TKI. Dr. Bunn presented preliminary data showing that a genome wide short hairpins(sh) RNA experiment identified FGFR as a synthetic lethal gene with EGFR TKI therapy, i.e., inhibition of FGFR (e.g., by AZ12908010) may enhance EGFR TKI activity. Dr. Sbar (Bristol-Myer Squibb) reported next the development of Brivanib, a dual vascular endothelial growth factor receptor and FGFR inhibitor in NSCLC. The IC50 of Brivanib for FGFR −1, −2, and −3 is between 60 and 150 nM, and it inhibits proliferation in vitro and angiogenesis in vivo in the L2987 lung cancer cell line model. FGFR signaling may also cause resistance to anti-vascular endothelial growth factor therapy. Result of phase 2 study has reported significant response to Brivanib + erlotinib in patients with heavily pretreated advanced KRAS wild-type colorectal cancer. A double-blinded/randomized withdrawal phase 2 study is being planned for patients with advanced stage treatment refractory NSCLC. Dr. David Spiegel (Vanderbilt) next discussed the FGFR monoclonal antibodies that are being developed for cancer therapy. These include AV-370 (anti-FGFR3) and FP-1039 (FGF trap) with limited in vitro cell line and in vivo results. He concluded that these novel biologics are still in their early phase development. The session concluded by discussion of the EPH/Ephrins especially EphB4 by Dr. Ravi Salgia (Chicago). Ephrins (ligand) and their receptors (Eph receptors) play important role in normal embryonic developmental processes such as vasculogenesis, cell migration, tissue-border formation, and axonal/synaptic network development. In tumors, they may promote cell proliferation, motility, invasion, metastasis, and angiogenesis. The expression of EpHA (nine members in human) and EphB (five members in human) are commonly induced in human malignancies. EphB4 overexpression has been reported in adeno and squamous carcinoma of the lung. Potential inhibitors include soluble inhibitor, monoclonal antibody, and small molecule inhibitors, although none of the latter has entered clinical study.