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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 European journal of cancer (Oxford, England : 1990)
Vol 61
Issue
Date 2016 07
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Alofanib RPT 835|RPT-835|RPT 835|ES000835 FGFR2 Inhibitor 19 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 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
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