Abstract SY42-02: Novel PET imaging in the clinic: Selecting patient cohorts and measuring early response
Authors: Eary Janet F. , Link Jeanne M. , Mankoff David A. , Muzi Mark , O'Sullivan Finbarr , Fink James R. , Rockhill Jason K. , Linden Hannah M. , Krohn Kenneth A. 
Published: August 2012

Molecular imaging with PET is most commonly associated with tumor detection and staging, currently with [F-18]-fluorodeoxyglucose (FDG-PET) to measure energy metabolism. However other imaging agents can be used to measure important characteristics of tumors that have the potential to guide in therapy selection or provide an early indication of response to therapy. Even though there are enthusiastic predictions of the role that “omics” biomarkers will play in personalized medicine, imaging biomarkers have some practical advantages over tissue and serum biomarkers. Imaging characterizes the entire tumor burden in the context of its environment and it can be repeated frequently. Several new PET agents are becoming widely available to probe important aspects of the tumor phenotype. The UW NCI-sponsored program project is developing PET to image tumor cancer biology with new agents that examine the tumor phenotype and how it changes in response to therapy.

There are many biological factors that can influence response of an individual patient to cancer therapy. Evaluation of these factors provides the questions and hypotheses posed in the UW PPG. The group focuses on investigations of reasons for poor tumor response to treatment. Hypoxia, cellular proliferation, low abundance of therapeutic targets (e.g. estrogen receptors) and acquired multidrug resistance (MDR/P-gp) are some of the imaging targets. These tumor variables can be quantified by PET imaging with [F-18]-fluoromisonidazole, [F-18]-3′-fluoro-3′-deoxythymidine, [F-18]-16α-fluoroestradiol and [C-11]-verapamil, respectively. Because hypoxia is a common characteristic of tumors but it is heterogeneous within a tumor mass and differs between tumor sites in a patient, imaging has an important role in assessing regional tumor tissue oxygenation. [F-18]-Fluoromisonidazole (FMISO) developed by our group is a PET hypoxia-imaging probe that accumulates at low PO2. Imaging results with this agent have demonstrated tumor hypoxic volume is an independent predictor of overall survival in patients with head and neck cancer, soft tissue sarcoma and primary brain tumors.

PET can also be used to image the response mechanism of a tumor to therapy. Current therapies are cytotoxic or cytostatic, with some combinations that are overlapping or aimed at a particular phosphokinase pathway. Uncontrolled tumor growth results from dysregulation of cellular proliferation and/or deficiencies in programmed cell death. FDG has been advocated for monitoring this net process but there are many contributors to energy metabolism in tumors, thus reducing the specificity of FDG-PET for evaluating tumor response. Thymidine and its analogs can be used to image the salvage pathway of cellular proliferation (DNA synthesis) with better specificity because these nucleosides are accumulated and phosphorylated during cellular S-phase. The UW PET group developed [F-18]-3′-fluoro-3′-deoxythymidine (FLT) for this purpose.

Our recent studies have focused on the challenge of distinguishing whether clinical symptoms and standard imaging appearance after therapy is predominantly a result of tumor progression or radionecrosis/pseudoprogression in patients with primary brain tumors. This application of FLT-PET emphasizes the value of dynamic imaging to separate the blood flow or delivery phase of the imaging agent from its tumor incorporation as a flux through the DNA salvage pathway. Segmentation algorithms and compartmental analyses are being used to generate parametric maps of regional tumor transport and synthetic flux. In several study results, the flux parametric image in recurrent brain tumors shows much higher FLT accumulation (salvage pathway activity) than in tumors with pseudo-progression whereas the transport images overlap between the two groups.

Imaging the P-gp drug resistance mechanism is performed using [C-11]-verapamil, a substrate for the transporter similar to the anthracyclines, which are the mainstay of many chemotherapy regimens. Preliminary work in sarcoma patients has shown that levels of P-gp activity are variable in tumors at presentation and change in response to therapy, usually resulting in an increase in activity. This increase in P-gp activity may confirm clinical suspicion that drug resistance has been induced in an individual as an important contributor to treatment resistance.

In summary, PET imaging provides an important tool for selecting patients with specific mechanisms of resistance to cancer therapy so that new drugs can be used with maximum effectiveness. PET imaging results can also provide useful biomarkers for tumor response to standard and experimental therapy, and will be important contributors towards the goal of personalized medicine for cancer patients. The UW PET group has worked with NCI-CIP to develop INDs for FMISO and FLT that are now used in multicenter trials. The group has also developed methods for analysis of FMISO and FLT images and provides a resource for image analysis in the trials. Both of these imaging agents, and approaches to acquiring and analyzing their images, are widely available to nuclear medicine clinical research groups to contribute toward progress in understanding cancer and its response to therapy.

The research results to be presented were supported by P01 CA042045-22.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY42-02. doi:1538-7445.AM2012-SY42-02