49P - Xentuzumab: targeting IGF1R/IR signalling in ER positive breast cancer

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Breast Cancer
Presenter Agnese Losurdo
Authors A. Losurdo1, N. O’donovan2, D. Winrow2, G. Gullo3, A. Santoro1, J. Crown3
  • 1Department Of Oncology, IRCCS Clinical and Research Institute Humanitas, 20089 - Rozzano/IT
  • 2Cellular Biotechnology, National Institute for Cellular Biotechnology, D9 - Dublin/IE
  • 3Medical Oncology Department, St Vincent's University Hospital, D4 - Dublin/IE

Abstract

Body

Background

Despite positive results in preclinical models, phase II trials testing anti-IGF1R monoclonal antibodies in oestrogen receptor (ER) positive breast cancer (BC) produced no significant increase in progression free survival [1,2]. The activation of insulin receptor (IR) has been implicated in resistance to anti-IGF1R therapy. Xentuzumab (BI 836845), a humanized monoclonal antibody with high affinity to human IGF1 and IGF2, resulted in effective inhibition of IGF-induced activation of both IGF1R and IR in vitro [3] and enhanced anti-tumour efficacy of rapamycin [4].

Materials and methods

Xentuzumab was tested in a panel of ER positive BC cell lines (MCF-7, T47D, CAMA-1), alone and in combination with hormonal therapy (e.g. tamoxifen, fulvestrant, oestrogen deprivation) and/or mTOR inhibitors (e.g. RAD 001). For proliferation assays, cells were seeded at 3 × 103 cells in 96-well plates and then treated with drug compounds . Cells were incubated for 5 days, then proliferation was calculated relative to untreated controls using the acid phosphatase assay. Each assay was carried out in biological triplicate.

Results

Xentuzumab (10 µg/mL) is active in MCF-7 (45% growth inhibition) and, to a lesser extent, in T47D cell lines (35% growth inhibition), while it does not exert any significant activity in CAMA-1 cells (5% growth inhibition), consistent with the known biological heterogeneity among luminal BC. In sensitive cell lines, the activity of fulvestrant, tamoxifen, and RAD 001 is potentiated by the addition of xentuzumab, the most powerful combination being xentuzumab, plus tamoxifen, plus RAD 001. In oestrogen deprivation conditions, mimicking the activity of an aromatase inhibitor, both xentuzumab and RAD 001 are more active than in the presence of oestradiol.

Conclusions

The activity of xentuzumab in luminal BC is promising and the potentiated growth inhibition of xentuzumab plus an mTOR inhibitor in oestrogen deprivation conditions supports the rationale for their development as a treatment strategy in vivo.

References

[1] Gradishar WJ et al. Clin Cancer Res. 2016

[2] Robertson JF et al. Lancet Oncol. 2013

[3] Mireuta M et al. Endocrinology. 2014

[4] Friedbichler K et al. Mol Cancer Ther. 2014

Clinical trial identification