Novel allosteric fibroblast growth factor receptor 2 (FGFR2) inhibitor alofanib has potent antitumor and antiangiogenic activity, according to results of preclinical studies presented at the ESMO Asia 2016 Congress in Singapore, 16-19 December 2016 (Abstract 151O). These data provide strong rationale for evaluation of compound in patients with FGFR2-expressing cancers.
“Alofanib is a novel first-in-class allosteric small-molecular inhibitor of FGFR2. Compound binds to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation,” said lead author Ilya Tsimafeyeu, MD, PhD, director of Kidney Cancer Research Bureau and Scientific Adviser of Ruspharmtech LLC (Russia). “The in vivo data are consistent with alofanib being a predominantly FGFR-selective inhibitor. In preclinical xenograft models, alofanib significantly inhibited aggressive growth of FGFR2 high-expressing triple-negative breast cancer and had moderate activity in the FGFR2 low-expressing triple-negative breast cancer. Treatment with alofanib did not result in the FGFR2-negative lung cancer growth. Accordingly, we believe that alofanib is capable of clinically testing an FGFR tumor-driven hypothesis, aiming to select patients based on deregulated tumor FGFR2 expression”.
“There is compelling evidence for deregulated FGF/FGFR2 signalling in the pathogenesis of many cancers that originate from different tissue types, for example, gastric and endometrial cancers. This study provides the first pharmacologic profile of the allosteric inhibitor alofanib with potential as a targeted antitumor therapy,” said Olivier Rixe, MD, PhD, Professor of the Division of Hematology/Oncology and Associate Director for Clinical Research, The Dana Wood Endowed Chair in Cancer Therapeutics and Early Phase Clinical Research, University of New Mexico Comprehensive Cancer Center (USA).
In the present study, authors showed that alofanib inhibited phosphorylation of FRS2α with IC50 values of 7 and 9 nmol/L in cancer cells expressing different FGFR2 isoforms (IIIc and IIIb). In a panel of cell lines representing several tumor types (triple negative breast cancer, melanoma, ovarian cancer), alofanib inhibited FGF-mediated proliferation.
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 tumor xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumor activity. Importantly, alofanib was effective in FGFR2-expressing models. For example, alofanib significantly inhibited aggressive growth of triple-negative breast cancer tumor xenograft (SUM 52PE). The tumor growth curve shows a nearly exponential increase in median tumor volume up to day 31 in the vehicle group and a high rate of slow growing tumors up to day 40 in the alofanib group.
Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. FGFR2 amplification and high-level polysomy may be a promising molecular target for serous ovarian cancer. FGFR2 amplification was found in 17.1 % of patients with advanced serous ovarian cancer. Thus, aim of presented xenograft studies was to increase efficacy of chemotherapy adding FGFR2 inhibitor alofanib.
As expected, intravenous alofanib significantly in dose-dependent manner potentiated the efficiency of the combination of paclitaxel and carboplatin. Daily intravenous regimen resulted in a 3-fold tumor growth delay in comparison with vehicle, and the inhibition rate of 80 % had been achieved. The proliferative index Ki-67 has been significantly reduced in mice treated with alofanib. In this study marked antiangiogenic activity in ovarian carcinoma model using combination of alofanib and chemotherapy was observed. Alofanib decreased number of vessels on 49 % and initiated vascular changes in tumors.
“In acute and chronic toxicity studies alofanib was well-tolerated. There was no treatment-related mortality, severe toxicity and significant changes in organs in the six months study. Body weight remained stable and it was comparable to vehicle groups. We found new side effect such as suppression of spermatogenesis. Spermatocytes express FGFR2 and theoretically alofanib could inhibit proliferation of these cells,” said Dr. Tsimafeyeu. “A phase Ib clinical study protocol has been selected for ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research, better known as the ‘Flims’ Workshop and clinical study will be initiated at the beginning of 2017”.
These studies were supported by a grant from Ruspharmtech LLC and Skolkovo Foundation.