Preclinical and Clinical Evidence that Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography with Computed Tomography Is a Reliable Tool for the Detection of Early Molecular Responses to Erlotinib in Head and Neck Cancer

Abstract

Purpose: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomography with computed tomography ( 18 FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity.Experimental Design: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in 18 FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the 18 FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed.Results: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in 18 FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses.Conclusion: These results show that the 18 FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma. Clin Cancer Res; 16(17); 4434-45. ©2010 AACR.

Changes in 18F-Fluorodeoxyglucose and 18F-Fluorodeoxythymidine Positron Emission Tomography Imaging in Patients with Non–Small Cell Lung Cancer Treated with Erlotinib

“…Our results about the utility of FDG-PET are concordant with the results from studies in other cancer types and/or utilizing other molecularly targeted therapies. For instance, a recent study in patients with head and neck cancer showed that FDG-PET was reliable for detection of early responses to erlotinib (40). Similar results were seen in a study of imatinib for treatment of gastrointestinal stromal tumors, and FDG-PET scans are now commonly used to assess responses in this setting (41).…”

K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis

“…In addition to its role in producing ATP, the glycolytic pathway may also provide important metabolic intermediates to be used for making biomass (nucleic acids, proteins, lipids) needed for cell growth and proliferation [2]. The increase in glucose uptake and utilization represents an important metabolic feature of cancer cells, and is clinically relevant since the majority of human cancers exhibit significant increase in glucose uptake in vivo , which can be readily detected by fluorodeoxy glucose-positron emission tomography (FDG-PET), an imaging method used in cancer diagnosis [3, 4]. Despite these long-standing observations, the exact molecular mechanisms responsible for the Warburg effect still remain unclear.…”

Formation of the eIF4F Translation–Initiation Complex Determines Sensitivity to Anticancer Drugs Targeting the EGFR and HER2 Receptors

“…1D). Furthermore, we used erlotinib, an EGFR tyrosine kinase inhibitor, on the human head and neck tumor cell line CAL33, which displays high EGFR expression (13). We developed CAL33-LTE by treating cells with increasing amounts of erlotinib for 6 months ( Supplementary Fig.…”