Abstract 2658: 18F-FLT PET imaging for noninvasive, early assessment of tumor response to MDM2-p53 disruption using a novel MDM2 inhibitor.

Abstract

Introduction: Potent, selective, and orally available small molecule inhibitors of the p53 regulator MDM2 represent a promising class of therapeutics. When applied to p53WT tumors, MDM2 inhibitors disrupt the MDM2-p53 interaction, thereby activating the p53 pathway and inducing cell cycle arrest and apoptosis. The aim of this study was to evaluate two clinically available PET tracers for their ability to monitor early response to treatment with a novel MDM2 inhibitor. Methods: 2’-Deoxy-2’-18F-fluoro-D-glucose (FDG) is used to measure glucose transport and hexokinase activity, and its use in cancer detection and response is based on the preferential glycolytic metabolism of tumor cells. 3′-Deoxy-3′-18F-fluoro-L-thymidine (FLT), an analog of thymidine, can measure nucleoside transport and thymidine kinase activity, which is upregulated in the S-phase of mitosis and can serve as a surrogate for cellular proliferation. Two p53WT in vivo tumor models were evaluated: (1) MDM2-amplified SJSA-1 human osteosarcoma xenografts which exhibit tumor regression upon MDM2 inhibitor treatment, and (2) MDM2-WT HCT116 human colon carcinoma xenografts which exhibit tumor stasis upon treatment. FDG and FLT PET scans (separate cohorts) were acquired (1) 24 hr before treatment with MDM2 inhibitor or vehicle (i.e., baseline), (2) after 6 hr and 72 hr of treatment, and (3) 72 hr after cessation of treatment (i.e., wash-out). Results: MDM2 inhibitor treatment resulted in comparable decreases in FDG and FLT tumor standardized uptake values (SUV) in SJSA-1 tumor xenografts at 6 hr post-treatment (-23% and -9% relative to baseline, respectively; P<0.01) that persisted throughout the 72 hr treatment (-52% and -34%, respectively; P<0.001) and 72 h wash-out period (-54%; P<0.0005 and -28%, respectively). In HCT116 xenografts, MDM2 inhibitor treatment significantly reduced FLT tumor SUV at 6 hr post-treatment (-32% relative to baseline, P<0.005) and persisted throughout the 72 hr treatment (-70%; P<0.001), and rebounded sharply by the end of the wash-out period in HCT116 xenografts (-32%; P<0.005). FDG tumor SUV was not significantly reduced at any timepoint in HCT116 xenografts. Conclusions: FDG and FLT PET imaging were roughly equivalent in ability to monitor efficacy of MDM2 inhibitor treatment in a SJSA-1 tumor regression model; however only FLT PET imaging revealed a treatment effect in the HCT116 tumor stasis model. FLT PET imaging was successfully used as a noninvasive tool to provide quantitative measurement of tumor response to treatment with a novel MDM2 inhibitor. These results suggest that FLT PET imaging could have utility as an early clinical pharmacodynamic biomarker. Citation Format: Tim Kazules, Becky Bryant, Matt Silva, Jude Canon, Charles Glaus. 18F-FLT PET imaging for noninvasive, early assessment of tumor response to MDM2-p53 disruption using a novel MDM2 inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2658. doi:10.1158/1538-7445.AM2013-2658