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Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-? degrader activity in antitumor efficacy.

ABSTRACT: PURPOSE:Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity. METHODS:Three xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation. RESULTS:A clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development. CONCLUSION:The use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.

SUBMITTER: Wardell SE

PROVIDER: S-EPMC6985185 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Wardell Suzanne E SE Yllanes Alexander P AP Chao Christina A CA Bae Yeeun Y Andreano Kaitlyn J KJ Desautels Taylor K TK Heetderks Kendall A KA Blitzer Jeremy T JT Norris John D JD McDonnell Donald P DP

Breast cancer research and treatment 20190927 1

<h4>Purpose</h4>Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patien ...[more]

PMID: 31562570

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Project description:Introduction: The flavonoid myricetin has been shown to induce cell cycle arrest and mitochondrial-dependent apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with redox properties and improved physicochemical attributes that enhance cell uptake and mitochondrial targeting might have increased potential as antitumour agents, since mitochondria are the main site of production of reactive oxygen species (ROS) and redox status is known to regulate the development and advancement of certain cancers. In this study we assessed a small library of novel flavonoids, then focussed on the lead compound, second-generation analogue OncamexTM, its mechanism of action and structure-activity relationships as an anti-proliferative agent. Methods: With this aim, we studied the effect of OncamexTM in a panel of 7 breast cancer cell lines using proliferation, cytotoxicity and apoptosis assays. The redox properties and mitochondrial delivery of the drug were studied using cyclic voltammetry and fluorescence microscopy, respectively. The mechanism of action was further studied using western blotting, gene expression analysis and immunohistochemistry (IHC) of treated xenograft tissue from in vivo mice models. Results: Sulforhodamine B (SRB) proliferation assays demonstrated strong, anti-proliferative properties of OncamexTM, with IC50 values in the low micromolar range. Treatment for 8 h exerted concentration-dependent reduction in cell viability and induction of cytotoxicity and apoptosis, with increased caspase activation. Microarray analysis suggested that OncamexTM regulates changes in cell cycle and apoptosis at gene expression level. Fluorescence microscopy was used to investigate mitochondrial targeting and ROS regulation in treated cells. OncamexTM was found to induce production of superoxide at concentrations which exerted anti-proliferative effects. Initial in vivo studies in mice implanted with a MDA-MB-231 breast cancer xenograft showed that OncamexTM inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusions: OncamexTM is a novel flavonoid capable of specific delivery to the mitochondria and induction of ROS production. We have shown its antitumor activity in preclinical models of breast cancer, both in vitro and in initial in vivo models, where tumour growth was arrested without inducing toxicity, support the potential of this novel drug for its continued development as an anticancer agent. Total RNA was obtained from 5 breast cancer cell lines subjected to 6 hours of 10µM OncamexTM and matched untreated controls (1% DMSO)

Dataset Information

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-? degrader activity in antitumor efficacy.

Publications

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Similar Datasets

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