Abstract 1758: Preclinical assessment of using [18F]FLT-PET imaging as a surrogate proof-of-mechanism biomarker for early drug development candidates

Abstract

Abstract [18F]FLT-PET imaging has been increasingly employed as a surrogate biomarker in early clinical trials to evaluate the mechanism of cancer drug candidates. In this report, we have assessed the preclinical application of [18F]FLT-PET imaging modality for several investigative agents that are currently under clinical development, including PF-03732010 (P-cadherin mAb), PD-0332991 (CDK4 inhibitor) and PF-03084014 (γ-secretase inhibitor). Docetaxel was also utilized as a standard comparator. Our goals included 1) building a preclinical understanding of the [18F]FLT tracer avidity in various xenograft models; 2) selecting models with appropriate tracer avidity and target molecular profiles for respective agents; 3) correlating suppression of [18F]FLT uptake with the changes of other pharmacodynamic endpoints and measures of antitumor efficacy; and 4) bridging preclinical and clinical [18F]FLT-PET imaging studies. Among the tested tumor models, [18F]FLT tracer avidity did not always correlate with the tumor growth rate. Affymetrix array and LC/MS analyses indicated that multiple factors including the expression levels of thymidine kinase 1 (TK1) and pyrimidine transporters, as well as the intrinsic thymidine level in tumor each contributed to the [18F]FLT tracer avidity. In the MDA-MB-435HAL-subrenal capsule model, administration of PF-03732010 resulted in a time- and dose-dependent inhibition of [18F]FLT tracer uptake, which corresponded with the modulation of β-catenin and Ki67 levels via IHC analysis. As β-catenin partners with P-cadherin for mediating the proliferation and invasiveness of tumor cells, this result suggests that the suppression in [18F]FLT uptake correspond with the target modulation. However, when we tested the [18F]FLT-PET imaging in the MDA-MB-231 model, treatment with an efficacious dose of PF-03084014 (GSI) exhibited an insignificant effect on the tracer uptake despite evidence in modulation of target genes. The GSI-induced impact on the tumor BrdU uptake was also minimal suggesting that the observed antitumor efficacy was not primarily mediated by modulation of cell cycle. In the Rb wild-type MDA-MB-231 and HCT116 tumor models, administration of an efficacious dose level of PD-0332991 (CDK4/6i) demonstrated a significant decline of [18F]FLT tracer uptake. Concurrent hypophosphorylation of RbSer780 and reduced BrdU uptake by IHC was also observed, indicating that [18F]FLT tracer uptake highly reflected the target modulation and predicted therapy. Therefore [18F]FLT-PET imaging modality presents a ideal proof-of-mechanism biomarker for PD-0332991. Collectively, these results indicate a potential applications for [18F]FLT-PET imaging in early clinical studies to demonstrate an impact on target endpoints depending on the mechanism of action of anticancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1758.