EJNMMI Research | 卷:10 |
Translational strategy using multiple nuclear imaging biomarkers to evaluate target engagement and early therapeutic efficacy of SAR439859, a novel selective estrogen receptor degrader | |
Sylvie Vincent1  Sébastien Roy2  Guillaume Bluet2  Cathy Aubert2  Sébastien d’Heilly2  Laurent Andrieu2  Erwan Jouannot2  Anne Caron2  Laurent Besret2  Chantal Carrez2  Carole Voland2  Florence Gruss-Leleu2  Françoise Le-Gall2  Jeffrey Ming3  Monsif Bouaboula3  Maysoun Shomali3  Srinivas Rao3  | |
[1] Present address: Takeda Pharmaceuticals; | |
[2] Sanofi Research and Development France; | |
[3] Sanofi Research and Development USA; | |
关键词: SAR439859; Estrogen-positive breast cancer; SERD; Target engagement; Combination therapy; Palbociclib; | |
DOI : 10.1186/s13550-020-00646-w | |
来源: DOAJ |
【 摘 要 】
Abstract Purpose Preclinical in vivo nuclear imaging of mice offers an enabling perspective to evaluate drug efficacy at optimal dose and schedule. In this study, we interrogated sufficient estrogen receptor occupancy and degradation for the selective estrogen receptor degrader (SERD) compound SAR439859 using molecular imaging and histological techniques. Material and methods [18F]FluoroEstradiol positron emission tomography (FES-PET), [18F]FluoroDeoxyGlucose (FDG) PET, and [18F]FluoroThymidine (FLT) PET were investigated as early pharmacodynamic, tumor metabolism, and tumor proliferation imaging biomarkers, respectively, in mice bearing subcutaneous MCF7-Y537S mutant ERα+ breast cancer model treated with the SERD agent SAR439859. ER expression and proliferation index Ki-67 were assessed by immunohistochemistry (IHC). The combination of palbociclib CDK 4/6 inhibitor with SAR439859 was tested for its potential synergistic effect on anti-tumor activity. Results After repeated SAR439859 oral administration over 4 days, FES tumoral uptake (SUVmean) decreases compared to baseline by 35, 57, and 55% for the 25 mg/kg qd, 12.5 mg/kg bid and 5 mg/kg bid treatment groups, respectively. FES tumor uptake following SAR439859 treatment at different doses correlates with immunohistochemical scoring for ERα expression. No significant difference in FDG uptake is observed after SAR439859 treatments over 3 days. FLT accumulation in tumor is significantly decreased when palbociclib is combined to SAR439859 (− 64%) but not different from the group dosed with palbociclib alone (− 46%). The impact on proliferation is corroborated by Ki-67 IHC data for both groups of treatment. Conclusions In our preclinical studies, dose-dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERα. FES-PET thus appears as a relevant imaging biomarker for measuring non-invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT-PET to directly visualize the anti-proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.
【 授权许可】
Unknown