[¹⁸F]Fluorodeoxyglucose Positron Emission Tomography Correlates With Akt Pathway Activity but Is Not Predictive of Clinical Outcome During mTOR Inhibitor Therapy

Abstract

Purpose Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models. Patients and Methods Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1. Results Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression. Conclusion FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

“…This is most likely explained by FDG-PET metabolic activity corresponding only to glucose uptake, and it does not measure a cells ability to proliferate or generate energy by alternate metabolic pathways such as via glutaminolysis (44). This has also been observed recently with mTOR inhibitors, where inhibition of PI3K/AKT pathway signaling and glucose metabolism was independent of tumor proliferation (45), and highlights the need to develop other PET tracers that correlate with drug target inhibition, tumor viability, and tumor proliferation. Despite the limitations of FDG-PET response to reflect the antitumor efficacy of PF-04691502, importantly, it does reflect successful target pathway inhibition and may therefore be a valuable biomarker of kinase inhibition during clinical development of this drug.…”

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

“…These techniques are being explored as tools for patient selection for several molecular-targeted drugs, including mTOR inhibitors. Thus far, [ 18 F]fluoro-2-deoxy-D-glucose PET (FDG-PET) measuring tumor glucose metabolism has received most attention (31,32). Inhibition of mTOR does indeed reduce glucose uptake by reducing glucose transporter 1 (GLUT1) expression and/or hexokinase activity (33).…”

“…according to European Organisation for Research and Treatment of Cancer (EORTC) criteria did not correlate with radiographic response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria or progressionfree survival in 34 patients with different cancer types treated with rapamycin (31). Given the role of mTOR in angiogenesis, we instead monitored the downstream effect of mTOR inhibition by everolimus on VEGF-A levels in xenografted ovarian cancers with 89 Zr-bevacizumab PET.…”

Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas

“…The precise mechanism of action of this effect is not known, but reduction of glucose uptake may be important. In this regard, mTOR inhibition with rapamycin has been shown to decrease glucose uptake by reducing the levels of Glut 1 in pancreas cancer (52,53).…”