An important pillar of precision medicine for oncology is the ability to identify patients who respond to treatment early into their therapy. Positron emission tomography (PET) allows physicians and researchers to measure changes in tumor behavior prior to noticeable differences in morphology. Objective: Determine the utility of multiple tracers for PET in assessing early changes in tumor activity that result from treatment. Methods: Two tracers for PET were studied. 64Cu-labeled liposomes were used to assess changes in liposome delivery two solid colon tumors early into treatment with bevacizumab (Bev). 18F-FMAU thymidine analog (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine), was utilized to detect early response to cisplatin treatment in non-small cell lung tumor models. Scans were analyzed before and after short-term therapy to determine changes in tracer retention which suggest therapeutic response. Results: In each study PET was able to detect changes in tumor behavior which occurred early into treatment. After two injections of Bev over one week, liposome delivery was significantly reduced as measured by PET. In lung tumors, 24 hours of cisplatin treatment induced significant drops in 18F-FMAU retention in cisplatin sensitive tumors compared to resistant tumors. Conclusion: PET imaging with a variety of tracers can provide information about tumor response to a broad spectrum of treatments. Thus, PET is a powerful tool for personalized therapy of cancer. Advisors/Committee Members: Anthony F. Shields.

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. Advisors/Committee Members: Anthony F. Shields.