Access Type

Open Access Dissertation

Date of Award

1-1-2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Anthony F. Shields

Abstract

Imaging is critical in the detection and management of malignancies, and positron emission tomography (PET) is an imaging approach that provides information regarding cancer physiology through the tracking of molecular pathways and receptors. 3’-fluoro-3’-deoxythymidine (FLT) is a PET tracer designed to image cellular proliferation, which is a hallmark of cancer. FLT has been used to study the response of cancer to a variety of treatments such as chemotherapy, targeted agents, and radiation.

Here we explored FLT retention as a biomarker to monitor the anti-proliferative effect of the synthetic glucocorticoid (GC) dexamethasone (Dex) on non-small cell lung cancer (NSCLC). The basis for this work was the recent finding that Dex can cause reversible cell cycle arrest in a subset of NSCLC cells leading to chemotherapy resistance. A similar phenomenon has been shown in several other solid tumor models treated with GCs. Through studies of cell line models, human xenografts, and NSCLC patients, we observed that although the susceptibility to Dex-mediated cell cycle arrest is variable between cancers, it could be detected using FLT-PET. We also examined the FLT ‘flare’ phenomenon, in which FLT uptake is transiently increased following treatment with drugs that reduce cellular thymidine synthesis. Two routinely used chemotherapeutic agents, pemetrexed and capecitabine, were found to produce marked increases in FLT accumulation, though the effect was variable in patients treated with capecitabine.

The success of FLT led to the introduction of other thymidine analog PET tracers including 1-(2’-deoxy-2’-fluoro-β-D-arabinofuranosyl) thymidine (FMAU) and 1-(2’-deoxy-2’-fluoro-β-D-arabinofuranosyl) uracil (FAU). Uptake of FMAU has been shown to be related to mitochondrial mass and cellular stress, while FAU is a prodrug that requires activation by thymidylate synthase. Although capecitabine treatment produced a change from baseline in patients imaged with FLT, tracer retention was unchanged in patients imaged with FMAU and FAU, highlighting the differences in imaging properties between the tracers.

In summary, FLT continues to show promise as a tool for the non-invasive monitoring of cellular proliferation, and may be a useful biomarker for the prediction of GC sensitivity in solid tumors.

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