Reference Detail

Ref Type

Journal Article

PMID

(27136102)

Authors

Tsimafeyeu I, Ludes-Meyers J, Stepanova E, Daeyaert F, Khochenkov D, Joose JB, Solomko E, Van Akene K, Peretolchina N, Yin W, Ryabaya O, Byakhov M, Tjulandin S

Title

Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	61		2016 07	20-8	Eur J Cancer

URL

Abstract Text

Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Alofanib	Alofanib	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Alofanib		RPT 835\|RPT-835\|RPT 835\|ES000835	FGFR2 Inhibitor 23	Alofanib (RPT835) is a small molecule that binds to the extracellular domain of Fgfr2 and inhibits downstream signaling, potentially resulting in decreased tumor cell proliferation (PMID: 27136102).

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
FGFR2 positive	triple-receptor negative breast cancer	sensitive	Alofanib	Preclinical - Cell culture	Actionable	In a preclinical study, Alofanib (RPT835) treatment led to inhibition of cell proliferation in triple-receptor negative breast cancer cell lines expressing FGFR2 in culture, and inhibited tumor growth in cell line xenograft models (PMID: 27136102).	27136102
FGFR2 positive	ovarian cancer	predicted - sensitive	Alofanib	Preclinical - Cell culture	Actionable	In a preclinical study, Alofanib (RPT835) inhibited growth in an ovarian cancer cell line expressing FGFR2 in culture (PMID: 27136102).	27136102