Work in KMB's laboratory is supported by a Cancer Research UK Programme grant (17242) and the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465). Clinical studies are funded by a Strategic Award from the Wellcome Trust (095962). E.M.S. was a recipient of a fellowship from the European Union Seventh Framework Programme (FP7/2007-2013) under the Marie Curie Initial Training Network METAFLUX (project number 264780). E.M.S. also acknowledges the educational support of the Programme for Advanced Medical Education from Calouste Gulbenkian Foundation, Champalimaud Foundation, Ministerio de Saude and Fundacao para a Ciencia e Tecnologia, Portugal. ; This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fonc.2016.00059
Measurements of hyperpolarized ¹³C label exchange between injected [1-¹³C]pyruvate and the endogenous tumor lactate pool can give an apparent first order rate constant for the exchange. Determination of isotope flux, however, requires an estimate of the labeled pyruvate concentration in the tumor. This was achieved here by measuring tumor uptake of [1-¹⁴C]pyruvate, which showed that <2% of the injected pyruvate reached the tumor site. Multiplication of this estimated labeled pyruvate concentration in the tumor with the apparent first order rate constant for hyperpolarized ¹³C label exchange gave an isotope flux that showed good agreement with a flux determined directly by injecting non polarized [3-¹³C]pyruvate and then rapidly excising the tumor after 30 s and measuring ¹³C-labeled lactate concentrations in tumor extracts. The distribution of labeled lactate between intra- and extracellular compartments and the blood pool was investigated by imaging, by measuring labeled lactate concentration in blood and tumor, and by examining the effects of a gadolinium contrast agent and a lactate transport inhibitor on the intensity of the hyperpolarized [1-¹³C]lactate signal. These measurements showed that there was significant export of labeled lactate from the tumor but that labeled lactate in the blood pool produced by injection of hyperpolarized [1-¹³C]pyruvate has only relatively low levels of polarization. This study has shown that measurements of hyperpolarized ¹³C label exchange between pyruvate and lactate in a murine tumor model can provide an estimate of the true isotope flux if the concentration of labeled pyruvate that reaches the tumor can be determined. ; This work was supported by a Cancer Research UK Programme grant (17242) awarded to K.M.B. and the Cancer Research UK & Engineering and Physical Sciences Research Council (CRUK-EPSRC) Imaging Centre in Cambridge and Manchester (16465). E.M.S. is a recipient of a fellowship from the European Union Seventh Framework Programme (FP7/2007-2013) under the Marie Curie Initial Training Network METAFLUX (project number 264780). T.B.R. is a recipient of an Intra-European Marie Curie (FP7-PEOPLE-2009-IEF, Imaging Lymphoma) fellowship and a Long-term European Molecular Biology Organization (EMBO-ALT-1145-2009) fellowship. E.M.S. acknowledges the educational support of the Programme for Advanced Medical Education from the Calouste Gulbenkian Foundation, Champalimaud Foundation, Ministerio de Saude and Fundacao para a Ciencia e Tecnologia, Portugal. The polarizer and related materials were provided by GE Healthcare. The polarimeter was provided by the National Institute for Health Research (NIHR) Cambridge Biomedical Centre. The laboratory is a member of and receives support from the CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester. This work was conducted under a research agreement with GE Healthcare. K.M.B. and M.I.K. hold patents with GE Healthcare on some aspects of the polarizer technology.
Whether for 13C magnetic resonance studies in chemistry, biochemistry or biomedicine, hyperpolarization methods based on dynamic nuclear polarization (DNP) have become ubiquitous. DNP requires a source of unpaired electrons, which are commonly added to the sample to be hyperpolarized in the form of stable free radicals. Once polarized, the presence of these radicals is unwanted. These radicals can be replaced by nonpersistent radicals created by photo-irradiation of pyruvic acid (PA), which are annihilated upon dissolution or thermalization in the solid state. However, since PA is readily metabolized by most cells, its presence may be undesirable for some metabolic studies. In addition, some 13C substrates are photo-sensitive and, therefore, may degrade during photo-generation of PA radical, which requires ultraviolet (UV) light. We show here that photoirradiation of phenylglyoxylic acid (PhGA) using visible light produces a non-persistent radical that, in principle, can be used to hyperpolarize any molecule. We compare radical yields in samples containing PA and PhGA upon photo-irradiation with broadband and narrowband UV-visible light sources. To demonstrate the suitability of PhGA as a radical precursor for DNP, we polarized the gluconeogenic probe 13C-dihydroxyacetone, which is UV-sensitive, using a commercial 3.35 T DNP polarizer and then injected this into a mouse and followed its metabolism in vivo. ; This work is part of a project that has received funding from the European Union's Horizon 2020 European Research Council (ERC Consolidator Grant) under grant agreement no. 682574 (ASSIMILES). Funding was also received from a Cancer Research UK Programme grant (17242) and from the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465). F.K. and S.P. received funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie grant agreement no. 642773 (EUROPOL). A. Capozzi received funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie grant agreement no. 713683 (COFUNDfellowsDTU).
Rapid cancer cell proliferation promotes the production of reducing equivalents, which counteract the effects of relatively high levels of reactive oxygen species (ROS). ROS levels increase in response to chemotherapy and cell death while an increase in antioxidant capacity can confer resistance to chemotherapy and is associated with an aggressive tumor phenotype. The pentose phosphate pathway (PPP) is a major site of NADPH production in the cell, which is used to maintain the main intracellular antioxidant, glutathione, in its reduced state. Previous studies have shown that the rate of hyperpolarized [1-$^{13}$C]dehydroascorbic acid (DHA) reduction, which can be measured $\textit{in vivo}$ using non-invasive $^{13}$C magnetic resonance spectroscopic imaging, is increased in tumors and that this is correlated with the levels of reduced glutathione. We show here that the rate of hyperpolarized [1-$^{13}$C]DHA reduction is increased in tumors that have been oxidatively pre-stressed by depleting the glutathione pool by buthionine sulfoximine treatment. This increase was associated with a corresponding increase in PPP flux, assessed using $^{13}$C-labeled glucose, and an increase in glutaredoxin activity, which catalyzes the glutathione-dependent reduction of DHA. These results show that the rate of DHA reduction does not depend only on the level of reduced glutathione, but also on the rate of NADPH production, contradicting the conclusions of some previous studies. Hyperpolarized [1-$^{13}$C]DHA can be used therefore to assess the capacity of tumor cells to resist oxidative stress in vivo. However, DHA administration resulted in transient respiratory arrest and cardiac depression, which may prevent translation to the clinic. ; Work in K.M. Brindle's laboratory is supported by a Cancer Research UK Programme grant (17242) and the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465). K.N. Timm was in receipt of MRC and Cancer Research UK studentships, B.W.C. Kennedy and P. Dzien Cancer Research UK studentships and F. Bulat a CRUK -EPSRC Imaging Centre imaging center studentship. I. Marco -Rius acknowledges the European Union Seventh Framework Programme (FP7/2007-2013) for support under the M arie Curie Initial Training Network METAFLUX (project number 264780).
Radioligand theranostics (RT) in oncology use cancer-type specific biomarkers and molecular imaging (MI), including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and planar scintigraphy, for patient diagnosis, therapy, and personalized management. While the definition of theranostics was initially restricted to a single compound allowing visualization and therapy simultaneously, the concept has been widened with the development of theranostic pairs and the combination of nuclear medicine with different types of cancer therapies. Here, we review the clinical applications of different theranostic radiopharmaceuticals in managing different tumor types (differentiated thyroid, neuroendocrine prostate, and breast cancer) that support the combination of innovative oncological therapies such as gene and cell-based therapies with RT. ; Funding: This work was partly funded by the Horizon 2020 Programme under grant agreement no 675417 (PET3D) and the Herbert-Worch-Stiftung. Additionally, this work was supported by a Collaboration Grant of the Medical Faculty of the University of Bonn between CIO UKB and the Johanniter Hospital. Acknowledgments: This review was supported by the Immune-Image consortium. The Immune- Image project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831514 (Immune-Image). The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
OBJECTIVES: Pancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging. DESIGN: The concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour. (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) was used to measure non-invasively changes in (13)C labelling of alanine and lactate with disease progression, following injection of hyperpolarised [1-(13)C]pyruvate. RESULTS: Progressive decreases in the alanine/lactate concentration ratio and ALT/LDH activity ratio with disease progression were accompanied by a corresponding decrease in the [1-(13)C]alanine/[1-(13)C]lactate signal ratio observed in (13)C-MRSI images of the pancreas. CONCLUSIONS: Metabolic imaging with hyperpolarised [1-(13)C]pyruvate enables detection and monitoring of the progression of PCa precursor lesions. Translation of this MRI technique to the clinic has the potential to improve the management of patients at high risk of developing PCa. ; The work was supported by a Cancer Research UK Programme grant (17242) to K.M.B. E.M.S. is a recipient of a fellowship from the European Union Seventh Framework Programme (FP7/2007-2013) under the Marie Curie Initial Training Network METAFLUX (project number 264780). T.B.R. is a recipient of an Intra- European Marie Curie (FP7-PEOPLE-2009-IEF, Imaging Lymphoma) fellowship and a Long-term European Molecular Biology Organization (EMBO-ALT-1145-2009) fellowship. E.M.S. and J.A. acknowledge the educational support of Programme for Advanced Medical Education from Calouste Gulbenkian Foundation, Champalimaud Foundation, Ministerio de Saude and Fundacao para a Ciencia e Tecnologia, Portugal. The polarizer and related materials were provided by GE Healthcare. The polarimeter was provided by NIHR Cambridge Biomedical Centre. The laboratory is a member of and receives support from the Cancer Research UK & Engineering and Physical Science Research Council Cancer Imaging Center in Cambridge and Manchester. The authors would also like to acknowledge Dr. Judit Espana, Dr. Athena Matakidou, Dr. Madhu Basetti, Dr. Jose Sandoval and Sarah McGuire for their help with experiments as well as the Tumor Models Core of Cancer Research UK-Cambridge Institute. ; This is the final version of the article. It first appeared from BMJ Group via http://dx.doi.org/10.1136/gutjnl-2015-310114
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
In: Kurhanewicz , J , Vigneron , D B , Ardenkjaer-Larsen , J H , Bankson , J A , Brindle , K , Cunningham , C H , Gallagher , F A , Keshari , K R , Kjaer , A , Laustsen , C , Mankoff , D A , Merritt , M E , Nelson , S J , Pauly , J M , Lee , P , Ronen , S , Tyler , D J , Rajan , S S , Spielman , D M , Wald , L , Zhang , X , Malloy , C R & Rizi , R 2019 , ' Hyperpolarized 13 C MRI : Path to Clinical Translation in Oncology ' , Neoplasia (New York, N.Y.) , vol. 21 , no. 1 , pp. 1-16 . https://doi.org/10.1016/j.neo.2018.09.006
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
In: Kurhanewicz , J , Vigneron , D B , Ardenkjaer-Larsen , J H , Bankson , J A , Brindle , K , Cunningham , C H , Gallagher , F A , Keshari , K R , Kjaer , A , Laustsen , C , Mankoff , D A , Merritt , M E , Nelson , S J , Pauly , J M , Lee , P , Ronen , S , Tyler , D J , Rajan , S S , Spielman , D M , Wald , L , Zhang , X , Malloy , C R & Rizi , R 2019 , ' Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology : Path to Clinical Translation in Oncology ' , NeoPlasia , vol. 21 , no. 1 , pp. 1-16 . https://doi.org/10.1016/j.neo.2018.09.006
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
In: Kurhanewicz , J , Vigneron , D B , Ardenkjær-Larsen , J H , Bankson , J A , Brindle , K , Cunningham , C H , Gallagher , F A , Keshari , K R , Kjær , A , Laustsen , C , Mankoff , D A , Merritt , M E , Nelson , S J , Pauly , J M , Lee , P , Ronen , S , Tyler , D J , Rajan , S S , Spielman , D M , Wald , L , Zhang , X , Malloy , C R & Rizi , R 2019 , ' Hyperpolarized 13 C MRI: Path to Clinical Translation in Oncology ' , NeoPlasia , vol. 21 , no. 1 , pp. 1-16 . https://doi.org/10.1016/j.neo.2018.09.006
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13 C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13 C MRI in 2011, preclinical studies involving [1- 13 C]pyruvate as well a number of other 13 C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1- 13 C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13 C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use. ; Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution.
