FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

Abstract

This study aimed to test whether [ 18 F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg À1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses X5 mg kg À1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg À1 per day and 57% for 15 mg kg À1 per day). Correspondingly, doses X5 mg kg À1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg À1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg À1 per day and 52% for 15 mg kg À1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.

Gastric Cancer Growth Control by BEZ235In VivoDoes Not Correlate with PI3K/mTOR Target Inhibition but with [18F]FLT Uptake

“…In the NCI-N87 xenografts, Ki67 expression did not differ between BEZ235-and Ctrltreated xenografts. Such contrasting results have been observed also in previous studies employing the NCI-N87 xenograft model, where no significant Ki67 suppression by mTOR inhibitors was observed despite antitumor activity and specific mTOR target regulation (24,46). As an alternative, we assessed TK1 expression which is likewise well established as a marker for cell proliferation (34).…”

“…PTEN loss was reported not to serve as a predictive biomarker for response to the mTOR inhibitor everolimus (45). Previous publications of our group showed that the phosphorylation status of the mTOR downstream target S6 does not necessarily predict efficacy of mTORC1 inhibitors in tumor models (44,46).…”

Measurement of Tumor VEGF-A Levels with 89Zr-Bevacizumab PET as an Early Biomarker for the Antiangiogenic Effect of Everolimus Treatment in an Ovarian Cancer Xenograft Model

“…Mice received 10 mg/kg everolimus daily via intraperitoneal injection (10 mL/kg). The everolimus dosage used is based on previous efficacy studies in xenografted mice, in which 5 to 10 mg/kg daily resulted in unbound (active) everolimus plasma levels comparable with those reached in humans receiving 5 to 10 mg daily due to higher plasma protein binding and shorter T 1/2 values in mice (8,(19)(20)(21)(22).…”

Everolimus: Emerging Evidence of its Therapeutic Impact in Patients with Advanced Renal Cell Carcinoma

“…40 In fact, changes in glucose uptake as measured by FDG PET imaging have been used to optimize everolimus dosing in vivo. 41 To address the possibility that changes in FDG-PET scanning may serve as an early predictor of response or resistance to everolimus treatment, a phase 2 trial is on-going in which 60 patients with metastatic RCC will undergo FDG-PET imaging before and after initiating therapy with everolimus. The primary objective of this study is to determine if high basal FDG-avidity is predictive of greater likelihood of response to everolimus as determined by changes in RECIST-based tumor measurements after 8 weeks of therapy.…”