Tim Witney is a Post-Doctoral Scholar and member of the Molecular Imaging Program at Stanford University.

He joined Professor Sanjiv Sam Gambhir's lab at Stanford in 2013, building on 3 years of postdoctoral research in biomedical imaging at Imperial College London and doctoral training at the University of Cambridge. His research interests include the discovery and development of new PET and MR methods to image tumour metabolism and the down-stream effect of targetted therapeutics. The development of a new generation of molecular imaging techniques will focus on early cancer detection, assess the efficacy of novel and preexisting cancer therapeutics and help describe the fundamental biological mechanisms that drive treatment resistance.

He was a finalist in MedImmune's 2009 Oncology Competition and has previously worked as a Research Biologist at GE Healthcare.

His blog on cancer imaging can be found at

Honors & Awards

  • Alavi-Mandell Award in recognition of outstanding articles published in JNM, The Society of Nuclear Medicine and Molecular Imaging (2015)
  • UCL Excellence Fellowship, University College London (2015)
  • SNMMI travel award, Society of Nuclear Medicine and Molecular Imaging (2014)
  • Sponsorship by Sofie Biosciences and Advanced Molecular Vision to attend conference, World Molecular Imaging Congress (2013)
  • Research selected for presentation in the ‘Highlight Lecture’, World Molecular Imaging Congress (2012)
  • Student Travel Stipend Award, World Molecular Imaging Congress (2012 & 2009)
  • Educational Stipend for Students, Postdoctoral, and Clinical Trainees, ISMRM (2010, 2009 & 2008)
  • Oncology Competition finalist, MedImmune (2009)
  • BBSRC/GE Healthcare-funded 4 year PhD CASE Studentship, Cambridge University (2006 – 2010)
  • University of Cambridge Post Graduate Research Fund, Homerton College (2007 – 2009)

Professional Education

  • Postdoctoral Scholar, Stanford University
  • Postdoctoral Research Associate, Imperial College London (2013)
  • Doctor of Philosophy, University of Cambridge (2010)
  • Bachelor of Science, University of Warwick (2006)

Stanford Advisors


Journal Articles

  • A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography. Cancer research Witney, T. H., Carroll, L., Alam, I. S., Chandrashekran, A., Nguyen, Q. D., Sala, R., Harris, R., Deberardinis, R. J., Agarwal, R., Aboagye, E. O. 2014; 74 (5): 1319-28


    The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized and is exploited with (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a noninvasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that (18)F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine ((18)F-NFTG) annotates glycogenesis in cancer cells and tumors in vivo, measured by PET. Specificity of glycogen labeling was demonstrated by isolating (18)F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1, which inhibited (18)F-NFTG uptake, whereas oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We further show that the rate of glycogenesis is cell-cycle regulated, enhanced during the nonproliferative state of cancer cells. We demonstrate that glycogen levels, (18)F-NFTG, but not (18)F-FDG uptake, increase proportionally with cell density and G1-G0 arrest, with potential application in the assessment of activation of oncogenic pathways related to glycogenesis and the detection of posttreatment tumor quiescence. Cancer Res; 74(5); 1319-28. ©2014 AACR.

    View details for DOI 10.1158/0008-5472.CAN-13-2768

    View details for PubMedID 24590807

  • Preclinical Evaluation of 3-18F-Fluoro-2,2-Dimethylpropionic Acid as an Imaging Agent for Tumor Detection. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Witney, T. H., Pisaneschi, F., Alam, I. S., Trousil, S., Kaliszczak, M., Twyman, F., Brickute, D., Nguyen, Q. D., Schug, Z., Gottlieb, E., Aboagye, E. O. 2014


    Deregulated cellular metabolism is a hallmark of many cancers. In addition to increased glycolytic flux, exploited for cancer imaging with (18)F-FDG, tumor cells display aberrant lipid metabolism. Pivalic acid is a short-chain, branched carboxylic acid used to increase oral bioavailability of prodrugs. After prodrug hydrolysis, pivalic acid undergoes intracellular metabolism via the fatty acid oxidation pathway. We have designed a new probe, 3-(18)F-fluoro-2,2-dimethylpropionic acid ((18)F-FPIA), for the imaging of aberrant lipid metabolism and cancer detection.Cell intrinsic uptake of (18)F-FPIA was measured in murine EMT6 breast adenocarcinoma cells. In vivo dynamic imaging, time course biodistribution, and radiotracer stability testing were performed. (18)F-FPIA tumor retention was further compared in vivo to (18)F-FDG uptake in several xenograft models and inflammatory tissue.(18)F-FPIA rapidly accumulated in EMT6 breast cancer cells, with retention of intracellular radioactivity predicted to occur via a putative (18)F-FPIA carnitine-ester. The radiotracer was metabolically stable to degradation in mice. In vivo imaging of implanted EMT6 murine and BT474 human breast adenocarcinoma cells by (18)F-FPIA PET showed rapid and extensive tumor localization, reaching 9.1% ± 0.5% and 7.6% ± 1.2% injected dose/g, respectively, at 60 min after injection. Substantial uptake in the cortex of the kidney was seen, with clearance primarily via urinary excretion. Regarding diagnostic utility, uptake of (18)F-FPIA was comparable to that of (18)F-FDG in EMT6 tumors but superior in the DU145 human prostate cancer model (54% higher uptake; P = 0.002). Furthermore, compared with (18)F-FDG, (18)F-FPIA had lower normal-brain uptake resulting in a superior tumor-to-brain ratio (2.5 vs. 1.3 in subcutaneously implanted U87 human glioma tumors; P = 0.001), predicting higher contrast for brain cancer imaging. Both radiotracers showed increased localization in inflammatory tissue.(18)F-FPIA shows promise as an imaging agent for cancer detection and warrants further investigation.

    View details for DOI 10.2967/jnumed.114.140343

    View details for PubMedID 25012458

  • Imaging as a pharmacodynamic and response biomarker in cancer Clinical and Translational Imaging Merchant, S., Witney, T. H., Aboagye, E. O. 2014; 2 (1): 13-31
  • Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by 18F-ICMT-11-Positron Emission Tomography. PloS one Witney, T. H., Fortt, R. R., Aboagye, E. O. 2014; 9 (3): e91694


    Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of 18F-ICMT-11 positron emission tomography - a method for detecting caspase 3/7 activation - in non-small cell lung cancer (NSCLC). 18F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in 18F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48h post carboplatin therapy. Average PET-derived tumour 18F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high 18F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by 18F-ICMT-11 PET.

    View details for DOI 10.1371/journal.pone.0091694

    View details for PubMedID 24618809

  • Synthesis of [F-18]fluoro-pivalic acid: an improved PET imaging probe for the fatty acid synthesis pathway in tumours MEDCHEMCOMM Pisaneschi, F., Witney, T. H., Iddon, L., Aboagye, E. O. 2013; 4 (10): 1350-1353

    View details for DOI 10.1039/c3md00169e

    View details for Web of Science ID 000324928100003

  • Design and synthesis of novel F-18-radiolabelled glucosamine derivatives for cancer imaging MEDCHEMCOMM Carroll, L., Witney, T. H., Aboagye, E. O. 2013; 4 (4): 653-656

    View details for DOI 10.1039/c3md00023k

    View details for Web of Science ID 000316868900003

  • Radiolabeled RGD Tracer Kinetics Annotates Differential αvβ 3 Integrin Expression Linked to Cell Intrinsic and Vessel Expression. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Alam, I. S., Witney, T. H., Tomasi, G., Carroll, L., Twyman, F. J., Nguyen, Q. D., Aboagye, E. O. 2013


    The purpose of this paper is to study the association between RGD binding kinetics and αvβ3 integrin receptor density in the complex tumor milieu.We assessed αvβ3 in vitro and by (68)Ga-DOTA-[c(RGDfK)]2 positron emission tomography (PET) in tumors with varying αvβ3.Intrinsic αvβ3 expression decreased in the order of M21 > MDA-MB-231 > M21L in cells. Tumor volume of distribution by PET, V T, was significantly higher in M21 compared to isogenic M21L tumors (0.40 ± 0.01 versus 0.25 ± 0.02; p < 0.01) despite similar microvessel density (MVD) likely due to higher αvβ3. V T for MDA-MB-231 (0.40 ± 0.04) was comparable to M21 despite lower αvβ3 but in keeping with the higher MVD, suggesting superior tracer distribution.This study demonstrates that radioligand binding kinetics of PET data can be used to discriminate tumors with different αvβ3 integrin expression-a key component of the angiogenesis phenotype-in vivo.

    View details for DOI 10.1007/s11307-013-0710-3

    View details for PubMedID 24310722

  • Magnetic resonance imaging with hyperpolarized [1,4-C-13(2)]fumarate allows detection of early renal acute tubular necrosis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Clatworthy, M. R., Kettunen, M. I., Hu, D., Mathews, R. J., Witney, T. H., Kennedy, B. W., Bohndiek, S. E., Gallagher, F. A., Jarvis, L. B., Smith, K. G., Brindle, K. M. 2012; 109 (33): 13374-13379


    Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.

    View details for DOI 10.1073/pnas.1205539109

    View details for Web of Science ID 000307807000053

    View details for PubMedID 22837393

  • Evaluation of Deuterated F-18- and C-11-Labeled Choline Analogs for Cancer Detection by Positron Emission Tomography CLINICAL CANCER RESEARCH Witney, T. H., Alam, I. S., Turton, D. R., Smith, G., Carroll, L., Brickute, D., Twyman, F. J., Quang-De Nguyen, Q. D., Tomasi, G., Awais, R. O., Aboagye, E. O. 2012; 18 (4): 1063-1072


    (11)C-Choline-positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts.(11)C-Choline, (11)C-methyl-[1,2-(2)H(4)]-choline ((11)C-D4-choline), and (18)F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft-bearing mice.Oxidation of choline analogs to betaine was highest with (11)C-choline, with reduced oxidation observed with (11)C-D4-choline and substantially reduced with (18)F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (K(i) and k(3)) of (11)C-choline and (11)C-D4-choline, compared with (18)F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of (18)F-D4-choline in three tumors with similar radiotracer delivery (K(1)) and choline kinase ? expression-HCT116, A375, and PC3-M-were the same, suggesting that (18)F-D4-choline has utility for cancer detection irrespective of histologic type.We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. (18)F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation.

    View details for DOI 10.1158/1078-0432.CCR-11-2462

    View details for Web of Science ID 000300628100016

    View details for PubMedID 22235095

  • Kinetic Modeling of Hyperpolarized C-13 Label Exchange between Pyruvate and Lactate in Tumor Cells JOURNAL OF BIOLOGICAL CHEMISTRY Witney, T. H., Kettunen, M. I., Brindle, K. M. 2011; 286 (28): 24572-24580


    Measurements of the kinetics of hyperpolarized (13)C label exchange between [1-(13)C]pyruvate and lactate in suspensions of intact and lysed murine lymphoma cells, and in cells in which lactate dehydrogenase expression had been modulated by inhibition of the PI3K pathway, were used to determine quantitatively the role of enzyme activity and membrane transport in controlling isotope flux. Both steps were shown to share in the control of isotope flux in these cells. The kinetics of label exchange were well described by a kinetic model that employed rate constants for the lactate dehydrogenase reaction that had been determined previously from steady state kinetic studies. The enzyme showed pyruvate inhibition in steady state kinetic measurements, which the kinetic model predicted should also be observed in the isotope exchange measurements. However, no such pyruvate inhibition was observed in either intact cells or cell lysates and this could be explained by the much higher enzyme concentrations present in the isotope exchange experiments. The kinetic analysis presented here shows how lactate dehydrogenase activity can be determined from the isotope exchange measurements. The kinetic model should be useful for modeling the exchange reaction in vivo, particularly as this technique progresses to the clinic.

    View details for DOI 10.1074/jbc.M111.237727

    View details for Web of Science ID 000292547900007

    View details for PubMedID 21596745

  • Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized C-13 Magnetic Resonance Spectroscopy MOLECULAR CANCER THERAPEUTICS Bohndiek, S. E., Kettunen, M. I., Hu, D., Witney, T. H., Kennedy, B. W., Gallagher, F. A., Brindle, K. M. 2010; 9 (12): 3278-3288


    Nuclear spin hyperpolarization can dramatically increase the sensitivity of the (13)C magnetic resonance experiment, allowing dynamic measurements of the metabolism of hyperpolarized (13)C-labeled substrates in vivo. Here, we report a preclinical study of the response of lymphoma tumors to the vascular disrupting agent (VDA), combretastatin-A4-phosphate (CA4P), as detected by measuring changes in tumor metabolism of hyperpolarized [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate. These measurements were compared with dynamic contrast agent-enhanced magnetic resonance imaging (DCE-MRI) measurements of tumor vascular function and diffusion-weighted MRI (DW-MRI) measurements of the tumor cell necrosis that resulted from subsequent loss of tumor perfusion. The rate constant describing flux of hyperpolarized (13)C label between [1-(13)C]pyruvate and lactate was decreased by 34% within 6 hours of CA4P treatment and remained at this lower level at 24 hours. The rate constant describing production of labeled malate from hyperpolarized [1,4-(13)C(2)]fumarate increased 1.6-fold and 2.5-fold at 6 and 24 hours after treatment, respectively, and correlated with the degree of necrosis detected in histologic sections. Although DCE-MRI measurements showed a substantial reduction in perfusion at 6 hours after treatment, which had recovered by 24 hours, DW-MRI showed no change in the apparent diffusion coefficient of tumor water at 6 hours after treatment, although there was a 32% increase at 24 hours (P < 0.02) when regions of extensive necrosis were observed by histology. Measurements of hyperpolarized [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate metabolism may provide, therefore, a more sustained and sensitive indicator of response to a VDA than DCE-MRI or DW-MRI, respectively.

    View details for DOI 10.1158/1535-7163.MCT-10-0706

    View details for Web of Science ID 000285296300017

    View details for PubMedID 21159611

  • Detecting treatment response in a model of human breast adenocarcinoma using hyperpolarised [1-C-13]pyruvate and [1,4-C-13(2)]fumarate BRITISH JOURNAL OF CANCER Witney, T. H., Kettunen, M. I., Hu, D., Gallagher, F. A., Bohndiek, S. E., Napolitano, R., Brindle, K. M. 2010; 103 (9): 1400-1406


    Background:The recent introduction of a dynamic nuclear polarisation technique has permitted noninvasive imaging of tumour cell metabolism in vivo following intravenous administration of (13)C-labelled cell substrates.Methods:Changes in hyperpolarised [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate metabolism were evaluated in both MDA-MB-231 cells and in implanted MDA-MB-231 tumours following doxorubicin treatment.Results:Treatment of MDA-MB-231 cells resulted in the induction of apoptosis, which was accompanied by a decrease in hyperpolarised (13)C label flux between [1-(13)C]pyruvate and lactate, which was correlated with a decrease in the cellular NAD(H) coenzyme pool. There was also an increase in the rate of fumarate conversion to malate, which accompanied the onset of cellular necrosis. In vivo, the decrease in (13)C label exchange between pyruvate and lactate and the increased flux between fumarate and malate, following drug treatment, were shown to occur in the absence of any detectable change in tumour size.Conclusion:We show here that the early responses of a human breast adenocarcinoma tumour model to drug treatment can be followed by administration of both hyperpolarised [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate. These techniques could be used, therefore, in the clinic to detect the early responses of breast tumours to treatment.

    View details for DOI 10.1038/sj.bjc.6605945

    View details for Web of Science ID 000283540300013

    View details for PubMedID 20924379

  • Imaging tumour cell metabolism using hyperpolarized C-13 magnetic resonance spectroscopy BIOCHEMICAL SOCIETY TRANSACTIONS Witney, T. H., Brindle, K. M. 2010; 38: 1220-1224


    Patients with similar tumour types frequently show different responses to the same therapy. The development of new treatments would benefit, therefore, from imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment. We have been using (13)C MRSI (magnetic resonance spectroscopic imaging) of tumour cell metabolism, using hyperpolarized (13)C-labelled cellular metabolites, to detect treatment response. Nuclear spin hyperpolarization can increase sensitivity in the magnetic resonance experiment >10,000 times, allowing us to image labelled cell substrates in vivo and their subsequent metabolism. We showed that exchange of hyperpolarized (13)C label between lactate and pyruvate, catalysed by lactate dehydrogenase, was decreased in treated tumours undergoing drug-induced cell death, and that tissue pH could be imaged from the ratio of the signal intensities of hyperpolarized H(13)CO(3)(-) and (13)CO(2) following intravenous injection of hyperpolarized H(13)CO(3). Tumour cell glutaminase activity, a potential measure of cell proliferation, can be determined using hyperpolarized [5-(13)C]glutamine, and treatment-induced tumour cell necrosis can be imaged in vivo from measurements of the conversion of hyperpolarized [1,4-(13)C(2)]fumarate into malate. Since these substrates are endogenous and, in some cases, have already been safely infused into patients, these techniques have the potential to translate to the clinic.

    View details for DOI 10.1042/BST0381220

    View details for Web of Science ID 000283039000009

    View details for PubMedID 20863288

  • Comparison of the C2A Domain of Synaptotagmin-I and Annexin-V As Probes for Detecting Cell Death BIOCONJUGATE CHEMISTRY Alam, I. S., Neves, A. A., Witney, T. H., Boren, J., Brindle, K. M. 2010; 21 (5): 884-891


    The induction of apoptosis is frequently accompanied by the exposure of phosphatidylserine (PS) on the cell surface, which has been detected using radionuclide and fluorescently labeled derivatives of the PS-binding protein, Annexin V. The fluorescently labeled protein has been used extensively in vitro as a diagnostic reagent for detecting cell death, and radionuclide-labeled derivatives have undergone clinical trials for detecting tumor cell death in vivo following treatment. We show here that the C2A domain of Synaptotagmin-I, which had been fluorescently labeled at a single cysteine residue introduced by site-directed mutagenesis, detected the same levels of cell death as a similarly labeled Annexin-V derivative, in drug-treated murine lymphoma and human breast cancer cell lines in vitro. However, the C2A derivative showed significantly less binding to viable cells and, as a consequence, up to 4-fold more specific binding to apoptotic and necrotic cells when compared with Annexin-V. C2A offers a potential route for the development of a new generation of more specific imaging probes for the detection of tumor cell death in the clinic.

    View details for DOI 10.1021/bc9004415

    View details for Web of Science ID 000277683300013

    View details for PubMedID 20402461

  • Magnetization Transfer Measurements of Exchange Between Hyperpolarized [1-C-13]Pyruvate and [1-C-13]Lactate in a Murine Lymphoma MAGNETIC RESONANCE IN MEDICINE Kettunen, M. I., Hu, D., Witney, T. H., McLaughlin, R., Gallagher, F. A., Bohndiek, S. E., Day, S. E., Brindle, K. M. 2010; 63 (4): 872-880


    Measurements of the conversion of hyperpolarized [1-(13)C]pyruvate into lactate, in the reaction catalyzed by lactate dehydrogenase, have shown promise as a metabolic marker for the presence of disease and response to treatment. However, it is unclear whether this represents net flux of label from pyruvate to lactate or exchange of isotope between metabolites that are close to chemical equilibrium. Using saturation and inversion transfer experiments, we show that there is significant exchange of label between lactate and pyruvate in a murine lymphoma in vivo. The rate constants estimated from the magnetization transfer experiments, at specific points during the time course of label exchange, were similar to those obtained by fitting the changes in peak intensities during the entire exchange time course to a kinetic model for two-site exchange. These magnetization transfer experiments may therefore provide an alternative and more rapid way of estimating flux between pyruvate and lactate to serial measurements of pyruvate and lactate (13)C peak intensities following injection of hyperpolarized [1-(13)C]pyruvate.

    View details for DOI 10.1002/mrm.22276

    View details for Web of Science ID 000276064300004

    View details for PubMedID 20373388

  • Production of hyperpolarized [1,4-C-13(2)]malate from [1,4-C-13(2)]fumarate is a marker of cell necrosis and treatment response in tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Gallagher, F. A., Kettunen, M. I., Hu, D., Jensen, P. R., in't Zandt, R., Karlsson, M., Gisselsson, A., Nelson, S. K., Witney, T. H., Bohndiek, S. E., Hansson, G., Peitersen, T., Lerche, M. H., Brindle, K. M. 2009; 106 (47): 19801-19806


    Dynamic nuclear polarization of (13)C-labeled cell substrates has been shown to massively increase their sensitivity to detection in NMR experiments. The sensitivity gain is sufficiently large that if these polarized molecules are injected intravenously, their spatial distribution and subsequent conversion into other cell metabolites can be imaged. We have used this method to image the conversion of fumarate to malate in a murine lymphoma tumor in vivo after i.v. injection of hyperpolarized [1,4-(13)C(2)]fumarate. In isolated lymphoma cells, the rate of labeled malate production was unaffected by coadministration of succinate, which competes with fumarate for transport into the cell. There was, however, a correlation with the percentage of cells that had lost plasma membrane integrity, suggesting that the production of labeled malate from fumarate is a sensitive marker of cellular necrosis. Twenty-four hours after treating implanted lymphoma tumors with etoposide, at which point there were significant levels of tumor cell necrosis, there was a 2.4-fold increase in hyperpolarized [1,4-(13)C(2)]malate production compared with the untreated tumors. Therefore, the formation of hyperpolarized (13)C-labeled malate from [1,4-(13)C(2)]fumarate appears to be a sensitive marker of tumor cell death in vivo and could be used to detect the early response of tumors to treatment. Given that fumarate is an endogenous molecule, this technique has the potential to be used clinically.

    View details for DOI 10.1073/pnas.0911447106

    View details for Web of Science ID 000272180900014

    View details for PubMedID 19903889

  • A Comparison between Radiolabeled Fluorodeoxyglucose Uptake and Hyperpolarized C-13-Labeled Pyruvate Utilization as Methods for Detecting Tumor Response to Treatment NEOPLASIA Witney, T. H., Kettunen, M. I., Day, S. E., Hu, D., Neves, A. A., Gallagher, F. A., Fulton, S. M., Brindle, K. M. 2009; 11 (6): 574-U88


    Detection of early tumor responses to treatment can give an indication of clinical outcome. Positron emission tomography measurements of the uptake of the glucose analog, [(18)F] 2-fluoro-2-deoxy-D-glucose (FDG), have demonstrated their potential for detecting early treatment response in the clinic. We have shown recently that (13)C magnetic resonance spectroscopy and spectroscopic imaging measurements of the uptake and conversion of hyperpolarized [1-(13)C]pyruvate into [1-(13)C]lactate can be used to detect treatment response in a murine lymphoma model. The present study compares these magnetic resonance measurements with changes in FDG uptake after chemotherapy. A decrease in FDG uptake was found to precede the decrease in flux of hyperpolarized (13)C label between pyruvate and lactate, both in tumor cells in vitro and in tumors in vivo. However, the magnitude of the decrease in FDG uptake and the decrease in pyruvate to lactate flux was comparable at 24 hours after drug treatment. In cells, the decrease in FDG uptake was shown to correlate with changes in plasma membrane expression of the facilitative glucose transporters, whereas the decrease in pyruvate to lactate flux could be explained by an increase in poly(ADP-ribose) polymerase activity and subsequent depletion of the NAD(H) pool. These results show that measurement of flux between pyruvate and lactate may be an alternative to FDG-positron emission tomography for imaging tumor treatment response in the clinic.

    View details for DOI 10.1593/neo.09254

    View details for Web of Science ID 000266360800007

    View details for PubMedID 19484146

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