Abstract
PurposePreclinical 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.ResultsAfter 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.ConclusionsIn 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.
Highlights
Both endogenous and exogenous steroid hormones such as estrogen and progesterone have been implicated in the pathogenesis of breast cancer
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%)
Based on ERα degradation kinetic profile, subjects receiving a single dose of SAR439859 were scanned 4 h after dosing (Tmax for FluoroEstradiol positron emission tomography (FES-Positron emission tomography (PET)) imaging at tumor SAR439859 Cmax) to determine the pharmacodynamic relationship between SAR439859 dose and ERα occupancy in MCF7-Y537S tumor-bearing mice
Summary
Both endogenous and exogenous steroid hormones such as estrogen and progesterone have been implicated in the pathogenesis of breast cancer. Given the efficacy of fulvestrant, the first-in-class intramuscular SERD compound, oral SERDs are likely to play an important role in therapeutic management of ER+ tumors This class of antagonists induces a degradation of the ERα receptor; their potential to block endocrine- and non-endocrine-dependent signaling has been recognized to offer a therapeutic approach in early-stage disease and improves outcomes for those with advanced ER+-resistant breast cancer [4, 5]. Fulvestrant exhibits both poor physicochemical and pharmacokinetic properties and the intramuscular route of administration has limited its use. A new generation of SERDs with improved properties is being currently developed [6,7,8]
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