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Ref Type Journal Article
PMID (23536011)
Authors Harding TC, Long L, Palencia S, Zhang H, Sadra A, Hestir K, Patil N, Levin A, Hsu AW, Charych D, Brennan T, Zanghi J, Halenbeck R, Marshall SA, Qin M, Doberstein SK, Hollenbaugh D, Kavanaugh WM, Williams LT, Baker KP
Title Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer.
Journal Vol Issue Date Pages Journal Short Title
Science translational medicine 5 178 2013 Mar 27 178ra39 Sci Transl Med
URL
Abstract Text The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)-induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039-mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or β-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.

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Molecular Profile Treatment Approach
FGFR1 amp GSK3052230
FGFR1 over exp GSK3052230
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp lung non-small cell carcinoma sensitive GSK3052230 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK3052230 (FP-1039) treatment inhibited growth of FGFR1 amplified non-small cell lung carcinoma cell lines in culture and in cell line xenograft models (PMID: 23536011). 23536011
FGFR2 S252W endometrial carcinoma sensitive GSK3052230 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK3052230 (FP-1039) treatment resulted in greater tumor growth inhibition (95% vs 30%) in cell line xenograft models of endometrial carcinoma harboring FGFR2 S252W compared to FGFR2 wild-type models (PMID: 23536011). 23536011
FGFR1 amp lung cancer sensitive GSK3052230 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK3052230 (FP-1039) treatment resulted in greater tumor growth inhibition (56% vs 22%) in cell line xenograft models of FGFR1 amplified lung cancer compared to FGFR1 non-amplified models (PMID: 23536011). 23536011
FGFR1 amp lung small cell carcinoma sensitive GSK3052230 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK3052230 (FP-1039) treatment inhibited growth of FGFR1 amplified lung small cell carcinoma cell lines in culture and in cell line xenograft models (PMID: 23536011). 23536011
FGFR1 amp lung small cell carcinoma sensitive Cisplatin + Etoposide + GSK3052230 Preclinical - Cell line xenograft Actionable In a preclinical study, addition of GSK3052230 (FP-1039) to Platinol (cisplatin) and Vepesid (etoposide) resulted in improved tumor growth inhibition in cell line xenograft models of FGFR1 amplified lung small cell carcinoma (PMID: 23536011). 23536011