Reference Detail

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 over exp	GSK3052230
FGFR1 amp	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 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	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
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 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 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