Metabolic shifts in disease are of great interest for the development of novel therapeutics. In cancer treatment, these therapies exploit the metabolic phenotype associated with oncogenesis and cancer progression.
One recent strategy involves the depletion of the cofactors needed to maintain the high rate of glycolysis seen with the Warburg effect. Specifically, blocking nicotinamide adenine dinucleotide (NAD) biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) inhibition depletes cancer cells of the NAD needed for glycolysis. To characterize this metabolic phenotype in vivo and describe changes in flux with treatment, non-invasive biomarkers are necessary. One such biomarker is hyperpolarized (HP) [1-(13) C] pyruvate, a clinically translatable probe that allows real-time assessment of metabolism.
We therefore developed a cell perfusion system compatible with HP magnetic resonance (MR) and positron emission tomography (PET) to develop translatable biomarkers of response to NAMPT inhibition in reduced volume cell cultures.
Using this platform, we observed a reduction in pyruvate flux through lactate dehydrogenase with NAMPT inhibition in prostate cancer cells, and showed that both HP lactate and 2-[(18) F] fluoro-2-deoxy-D-glucose (FDG) can be used as biomarkers for treatment response of such targeted agents. Moreover, we observed dynamic flux changes whereby HP pyruvate was re-routed to alanine, providing both positive and negative indicators of treatment response.
This study demonstrated the feasibility of a MR/PET compatible bioreactor approach to efficiently explore cell and tissue metabolism, the understanding of which is critical for developing clinically translatable biomarkers of disease states and responses to therapeutics. Prostate 75:1601-1609, 2015. © 2015 Wiley Periodicals, Inc.
The Prostate. 2015 Jul 14 [Epub]
Kayvan R Keshari, David M Wilson, Mark Van Criekinge, Renuka Sriram, Bertram L Koelsch, Zhen J Wang, Henry F VanBrocklin, Donna M Peehl, Tom O'Brien, Deepak Sampath, Richard A D Carano, John Kurhanewicz
Department of Radiology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. , Department of Urology, Stanford University, Stanford, California. , Department of Translational Oncology, Genentech Inc. , South San Francisco, California. , Department of Translational Oncology, Genentech Inc. , South San Francisco, California. , Department of Biomedical Imaging, Genentech Inc. , South San Francisco, California. , Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.