Besret Laurent, d'Heilly Sébastien, Aubert Cathy, Bluet Guillaume, Gruss-Leleu Florence, Le-Gall Françoise, Caron Anne, Andrieu Laurent, Vincent Sylvie, Shomali Maysoun, Bouaboula Monsif, Voland Carole, Ming Jeffrey, Roy Sébastien, Rao Srinivas, Carrez Chantal, Jouannot Erwan
Sanofi Research and Development France, 13 quai Jules Guesde, 94403, Vitry-sur-Seine, France.
Present address: Takeda Pharmaceuticals, 35 Landsdowne St, Cambridge, MA, 02139, USA.
EJNMMI Res. 2020 Jun 29;10(1):70. doi: 10.1186/s13550-020-00646-w.
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.
[F]FluoroEstradiol positron emission tomography (FES-PET), [F]FluoroDeoxyGlucose (FDG) PET, and [F]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.
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.
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.
小鼠临床前体内核成像为评估最佳剂量和给药方案下的药物疗效提供了一个可行的视角。在本研究中，我们使用分子成像和组织学技术探究了选择性雌激素受体降解剂（SERD）化合物SAR439859的雌激素受体占有率和降解情况。
分别将[F]氟雌二醇正电子发射断层扫描（FES-PET）、[F]氟脱氧葡萄糖（FDG）PET和[F]氟胸苷（FLT）PET作为早期药效学、肿瘤代谢和肿瘤增殖成像生物标志物，用于接受SERD药物SAR439859治疗的皮下接种MCF7-Y537S突变型ERα+乳腺癌模型小鼠。通过免疫组织化学（IHC）评估ER表达和增殖指数Ki-67。测试了帕博西尼CDK 4/6抑制剂与SAR439859联合使用对抗肿瘤活性的潜在协同作用。
在4天内重复口服SAR439859后，对于25mg/kg每日一次、12.5mg/kg每日两次和5mg/kg每日两次治疗组，FES肿瘤摄取量（SUVmean）与基线相比分别降低了35%、57%和55%。不同剂量的SAR439859治疗后FES肿瘤摄取量与ERα表达的免疫组织化学评分相关。在3天的SAR439859治疗后，未观察到FDG摄取有显著差异。当帕博西尼与SAR439859联合使用时，肿瘤中的FLT积累显著降低（-64%），但与单独给予帕博西尼的组（-46%）无差异。两组治疗的Ki-67 IHC数据证实了对增殖的影响。
在我们的临床前研究中，FES肿瘤摄取的剂量依赖性抑制证实了SAR439859与ERα的靶点结合。因此，FES-PET似乎是一种相关的成像生物标志物，可用于无创测量SAR439859对肿瘤雌激素受体占有率的影响。本研究进一步验证了FLT-PET用于直接可视化帕博西尼CDK 4/6抑制剂单独使用以及与SAR439859联合使用时的抗肿瘤增殖作用。
