PET with 18F-FDG and 18F-FMAU in the assessment of early response to EGFR-targeted therapy in mice bearing human NSCLC xenografts with different EGFR mutations

Abstract

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Objectives: This study aimed to assess the efficacy of PET imaging for monitoring early changes in glucose metabolism with 18F-FDG and proliferative activity with 18F-FMAU in human NSCLC xenografts in mice in response to therapy with EGFR kinase inhibitor gefitinib.

Methods: Human lung carcinoma cells PC14, H441, H3255, and H1975, expressing different EGFR mutants and various levels of TGFα (Tab. 1), were injected s.c. (3x106 cells) in nu/nu mice. When tumors grew >5 mm in diameter, PET imaging with 18F-FDG and 18F-FMAU was performed on two consecutive days and repeated after 3 and 4 days of gefitinib (100 mg/kg) therapy, respectively. Tumor growth was monitored by calipers.

Results: Tumor-to-muscle (T/M) ratios of 18F-FDG and 18F-FMAU accumulation for different NSCLC xenografts before and after gefitinib treatment are summarized in Table 1. Pre-treatment T/M ratios of 18F-FMAU were higher than those of 18F-FDG, especially in gefitinib-resistant NSCLCs (PC14, H1975). In these tumors, the lack of decrease in 18F-FMAU and 18F-FDG T/M ratios after 3-4 days of gefitinib therapy was predictive of tumor resistance, as evidenced by progression of tumor growth during the following 12 days of therapy with gefitinib. In gefitinib-sensitive tumors (H441 and H3255), no significant changes in 18F-FDG and 18F-FMAU T/M ratios after 3-4 days of gefitinib therapy have been observed, because of the low pre-treatment T/M ratios of both radiotracers, especially in H3255 carcinomas, which had almost complete response at 12 days of gefitinib therapy.

Conclusions: PET with 18F-FMAU demonstrated higher sensitivity for the detection of NSCLCs as compared to 18F-FDG. The lack of decrease in 18F-FDG and 18F-FMAU uptake early after initiation of gefitinib therapy is predictive of tumor resistance. However, in some gefitinib sensitive NSCLCs the assessment of early treatment responses by PET may not be feasible, because of very low pre-treatment levels of uptake of both 18F-FDG and 18F-FMAU. Therefore, alternative imaging agents need to be developed for the detection of NSCLCs and for monitoring molecular-targeted therapies in patients.

Research Support (if any): This work was supported by the DOD grant W81XWH-05-2-0027.

Table 1