Production of deoxyribonucleoside triphosphate (dNTP) precursors for DNA synthesis is critical for cell proliferation and genomic integrity. Two biosynthetic pathways contribute to cellular dNTP pools: de novo synthesis and deoxyribonucleoside salvage. This application focuses on deoxycytidine kinase (DCK), a key enzyme in the salvage pathway. DCK has unique properties: it provides cells with all 4 dNTPs and is essential for the activation of nucleoside analog drugs used in cancer. We hypothesize that the enzymatic activity of DCK can be imaged by Positron Emission Tomography (PET) and that PET assays that measure DCK may allow stratification of cancer patients for treatment with nucleoside analog drugs. To test these hypotheses we propose a multidisciplinary project that combines genetic, molecular biology, biochemical and molecular imaging approaches to investigate the biological function of DCK and to develop PET probes to monitor its activity in vivo. This work leverages tools and reagents identified in the current ICMIC cycle;we developed [  F]-1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine ([ F] FAC), a new DCK substrate PET probe, using a new approach to identify potential imaging agents. The team of proposed investigators has combined excellence in cancer biology, molecular biology, biochemistry, radiochemistry, preclinical and clinical molecular imaging. The strength of this collaboration is demonstrated by the fact that in the last 24 months we have taken a series of PET probes from extensive in vitro selection and evaluation to in vivo PET investigations in mice, and then to patients. This project will use all three ICMIC Specialized Resources.
In Specific Aim 1 we will develop a novel experimental model that allows conditional inactivation of the DCK gene in mice. The DCK deficient mice will be used to validate the tissue retention of [ F] FAC as an accurate non-invasive measurement of DCK activity in vivo and to interpret the results of PET assays using DCK-specific probes.
In Specific Aim 2 we will design, synthesize and evaluate optimized [ F] FAC probes.
Specific Aim 3 proposes the clinical translation of DCK-specific probes and the development of new molecular imaging approaches to predict tumor responses to DCK-dependent drugs.
The scientific yield from this project should widen the utility of molecular imaging approaches and may lead to improved therapies for cancer, significantly impacting public health. Moreover, this project provides a path by which new non-invasive molecular imaging diagnostic probes and assays are discovered, developed and translated to the clinic to yield approaches for stratification of treatment options in cancer.
|Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914|
|Balandeh, Mehrdad; Waldmann, Christopher; Shirazi, Daniela et al. (2017) Electrochemical Fluorination and Radiofluorination of Methyl(phenylthio)acetate Using Tetrabutylammonium Fluoride (TBAF). J Electrochem Soc 164:G99-G103|
|Waldmann, Christopher M; Lebedev, Artem; Allison, Nathaniel et al. (2017) An automated synthesizer for electrochemical 18F-fluorination of organic compounds. Appl Radiat Isot 127:245-252|
|Lee, Jason T; Zhang, Hanwen; Moroz, Maxim A et al. (2017) Comparative Analysis of Human Nucleoside Kinase-Based Reporter Systems for PET Imaging. Mol Imaging Biol 19:100-108|
|Barrio, Martin; Czernin, Johannes; Yeh, Michael W et al. (2016) The incidence of thyroid cancer in focal hypermetabolic thyroid lesions: an 18F-FDG PET/CT study in more than 6000 patients. Nucl Med Commun 37:1290-1296|
|Tavaré, Richard; Escuin-Ordinas, Helena; Mok, Stephen et al. (2016) An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy. Cancer Res 76:73-82|
|Kirkby, Nicholas S; Chan, Melissa V; Zaiss, Anne K et al. (2016) Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-?B and NFAT transcriptional pathways. Proc Natl Acad Sci U S A 113:434-9|
|Kim, Woosuk; Le, Thuc M; Wei, Liu et al. (2016) [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Proc Natl Acad Sci U S A 113:4027-32|
|Faltermeier, Claire M; Drake, Justin M; Clark, Peter M et al. (2016) Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A 113:E172-81|
|Clark, Peter M; Mai, Wilson X; Cloughesy, Timothy F et al. (2016) Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma. Curr Neurol Neurosci Rep 16:17|
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