Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Monitoring early efficacy of PI3K/mTOR targeted cancer therapies using 18F-FPHCys, a new potential imaging biomarker (#212)

Delphine Denoyer 1 , Peter Roselt 1 , Thomas Bourdier 2 , Andrew Katsifis 2 , Rodney J Hicks 1
  1. Molecular Imaging and Targeted Therapeutics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Department PET and nuclear medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Background: A major challenge facing clinicians who treat cancer patients with new molecular targeted drugs, such as PI3K/mTOR inhibitors is to assess early response to treatment. Positron Emission Tomography (PET) has emerged as an excellent imaging modality to assess early drug efficacy to such agents. However, there are currently no reliable imaging biomarkers available to monitor PI3K/mTOR targeting treatment by PET. Our team developed a new 18F-labelled methionine derivative, 18F-FPHCys with excellent potential for imaging solid tumours and uptake in cancer cells mediated primarily by the LAT1 system-L amino acid transporter. Given the well-characterised role of PI3K/mTOR in the regulation of protein synthesis, we hypothesised that inhibition of PI3K/mTOR may impact on amino acid uptake by modulating LAT1 activity and/or expression. If so, PI3K/mTOR inhibitors would be expected to decrease 18F-FPHCys accumulation in cancer cells.

Aim: The aim of this study is to investigate the potential of 18F-FPHCys as a non-invasive biomarker to demonstrate the anti-tumour activity of PI3K/mTOR inhibitors.

Material and Methods: 18F-FPHCys uptake was assessed in various human cancer cell lines following 24-, 48- or 72-hours treatment with an mTORC1 inhibitor, a dual mTORC1/mTORC2 inhibitor or a dual PI3K/mTOR inhibitor. LAT1 expression was measured by immunoblot.

Results: The preliminary results obtained with PC3 cells show a marked inhibition of 18F-FPHCys uptake as early as 24 hours following treatment with either of the inhibitors, which is even more pronounced after 72 hours. Decreased 18F-FPHCys accumulation is associated with decreased LAT1 expression but not with cell proliferation status. None of the inhibitors tested impacted on cell viability. The results with other cell lines will be further discussed at the meeting.

Conclusion: These results suggest the importance of mTOR for the regulation of amino acid transport and that 18F-FPHCys has the potential to monitor the early effects of PI3K/mTOR inhibition on tumour metabolism.