EXPLORING CANCER METABOLIC REPROGRAMMING THROUGH MOLECULAR IMAGING EDITED BY : Franca Podo, Zaver M. Bhujwalla and Egidio Iorio PUBLISHED IN : Frontiers in Oncology 1 Frontiers in Oncology July 2017 | Exploring Cancer Metabolic Reprogramming Frontiers Copyright Statement © Copyright 2007-2017 Frontiers Media SA. All rights reserved. All content included on this site, such as text, graphics, logos, button icons, images, video/audio clips, downloads, data compilations and software, is the property of or is licensed to Frontiers Media SA (“Frontiers”) or its licensees and/or subcontractors. The copyright in the text of individual articles is the property of their respective authors, subject to a license granted to Frontiers. The compilation of articles constituting this e-book, wherever published, as well as the compilation of all other content on this site, is the exclusive property of Frontiers. 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Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: researchtopics@frontiersin.org EXPLORING CANCER METABOLIC REPROGRAMMING THROUGH MOLECULAR IMAGING Topic Editors: Franca Podo, Istituto Superiore di Sanità, Italy Zaver M. Bhujwalla, The Johns Hopkins University School of Medicine, USA Egidio Iorio, Istituto Superiore di Sanità, Italy The inclusion of oncogene-driven reprogramming of energy metabolism within the list of cancer hallmarks (Hanahan and Weinberg, Cell 2000, 2011) has provided major impetus to further investigate the existence of a much wider metabolic rewiring in cancer cells, which not only includes deregulated cellular bioenergetics, but also encompasses multiple links with a more comprehensive network of altered biochemical pathways. This network is currently held responsible for redirecting carbon and phosphorus fluxes through the biosynthesis of nucleotides, amino acids, lipids and phospholipids and for the production of second messengers essential to cancer cells growth, survival and invasiveness in the hostile tumor environment. The capability to develop such a concerted rewiring of biochemical pathways is a versatile tool adopted by cancer cells to counteract the host defense and eventually resist the attack of anticancer treatments. Integrated efforts elucidating key mechanisms underlying this complex cancer metabolic reprogramming have led to the identification of new signatures of malignancy that are providing a strong foundation for improving cancer diagnosis and monitoring tumor response to therapy using appropriate molecular imaging approaches. In particular, the recent evolution of positron emission tomography (PET), magnetic resonance spectroscopy (MRS), magnetic resonance spectroscopic imaging (MRSI), functional magnetic resonance imaging (fMRI) and optical imaging technologies, combined with complementary cellular imaging approaches, have created new ways to explore and monitor the effects of Cover Photo: “Evoking interactive pathways in a metabolic network” by Giuseppe Fossati Lenz cloth composition (14.0 × 11.5 cm) San Donato Milanese Exhibition, 2013, Milan, Italy. Courtesy by the Artist to Frontiers in Oncology, Research Topic “Exploring Cancer Metabolic Reprogramming through Molecular Imaging”. 2 Frontiers in Oncology July 2017 | Exploring Cancer Metabolic Reprogramming metabolic reprogramming in cancer at clinical and preclinical levels. Thus, the progress of high-tech engineering and molecular imaging technologies, combined with new generation genomic, proteomic and phosphoproteomic methods, can significantly improve the clinical effectiveness of image-based interventions in cancer and provide novel insights to design and validate new targeted therapies. The Frontiers in Oncology Research Topic “Exploring Cancer Metabolic Reprogramming Through Molecular Imaging” focusses on current achievements, challenges and needs in the application of molecular imaging methods to explore cancer metabolic reprogramming, and evaluate its potential impact on clinical decisions and patient outcome. A series of reviews and perspective articles, along with original research contributions on humans and on preclinical models have been concertedly included in the Topic to build an open forum on perspectives, present needs and future challenges of this cutting-edge research area. Citation: Podo, F., Bhujwalla, Z. M., Iorio, E., eds. (2017). Exploring Cancer Metabolic Reprogramming Through Molecular Imaging. Lausanne: Frontiers Media. doi: 10.3389/978-2-88945-234-7 3 Frontiers in Oncology July 2017 | Exploring Cancer Metabolic Reprogramming 07 Editorial: Exploring Cancer Metabolic Reprogramming through Molecular Imaging Franca Podo, Zaver M. Bhujwalla and Egidio Iorio Exploring the Links of Cancer Metabolic Reprogramming with Tumor Progression and Response to Therapy Using Molecular Imaging Approaches: Present Views and Perspectives 11 Potential Clinical Roles for Metabolic Imaging with Hyperpolarized [1- 13 C]Pyruvate Eva M. Serrao and Kevin M. Brindle 17 Positron Emission Tomography Imaging of Tumor Cell Metabolism and Application to Therapy Response Monitoring Amarnath Challapalli and Eric O. Aboagye 37 13 C MRS and LC–MS Flux Analysis of Tumor Intermediary Metabolism Alexander A. Shestov, Seung-Cheol Lee, Kavindra Nath, Lili Guo, David S. Nelson, Jeffrey C. Roman, Dennis B. Leeper, Mariusz A. Wasik, Ian A. Blair and Jerry D. Glickson 60 Molecular Imaging of Metabolic Reprograming in Mutant IDH Cells Pavithra Viswanath, Myriam M. Chaumeil and Sabrina M. Ronen 68 Targeting Phospholipid Metabolism in Cancer Menglin Cheng, Zaver M. Bhujwalla and Kristine Glunde 85 The Tumor Microenvironment Modulates Choline and Lipid Metabolism Noriko Mori, Flonné Wildes, Tomoyo Takagi, Kristine Glunde and Zaver M. Bhujwalla 95 Characterization of the Tumor Microenvironment and Tumor–Stroma Interaction by Non-invasive Preclinical Imaging Nirilanto Ramamonjisoa and Ellen Ackerstaff 117 Potential of Induced Metabolic Bioluminescence Imaging to Uncover Metabolic Effects of Antiangiogenic Therapy in Tumors Stefano Indraccolo and Wolfgang Mueller-Klieser 123 Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy Franca Podo, Luisa Paris, Serena Cecchetti, Francesca Spadaro, Laura Abalsamo, Carlo Ramoni, Alessandro Ricci, Maria Elena Pisanu, Francesco Sardanelli, Rossella Canese and Egidio Iorio Table of Contents 4 Frontiers in Oncology July 2017 | Exploring Cancer Metabolic Reprogramming 131 Metabolic Imaging to Assess Treatment Response to Cytotoxic and Cytostatic Agents Natalie J. Serkova and S. Gail Eckhardt Challenges and Future Directions in the Application of Metabolic Imaging Approaches to Preclinical Models and to Cancer Patients Breast Cancer 140 Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status Adi Pais and Hadassa Degani 153 Key Players in Choline Metabolic Reprograming in Triple-Negative Breast Cancer Egidio Iorio, Maria José Caramujo, Serena Cecchetti, Francesca Spadaro, Giulia Carpinelli, Rossella Canese and Franca Podo 161 Impact of Freezing Delay Time on Tissue Samples for Metabolomic Studies Tonje H. Haukaas, Siver A. Moestue, Riyas Vettukattil, Beathe Sitter, Santosh Lamichhane, Remedios Segura, Guro F . Giskeødegård and Tone F . Bathen 170 Metabolic Study of Breast MCF-7 Tumor Spheroids after Gamma Irradiation by 1 H NMR Spectroscopy and Microimaging Alessandra Palma, Sveva Grande, Anna Maria Luciani, Vladimír Mlynárik, Laura Guidoni, Vincenza Viti and Antonella Rosi 179 Glycerophosphocholine and Glycerophosphoethanolamine Are Not the Main Sources of the In Vivo 31 P MRS Phosphodiester Signals from Healthy Fibroglandular Breast Tissue at 7 T Wybe J. M. van der Kemp, Bertine L. Stehouwer, Jurgen H. Runge, Jannie P . Wijnen, Aart J. Nederveen, Peter R. Luijten and Dennis W. J. Klomp 186 Potential of Diffusion-Weighted Imaging in the Characterization of Malignant, Benign, and Healthy Breast Tissues and Molecular Subtypes of Breast Cancer Uma Sharma, Rani G. Sah, Khushbu Agarwal, Rajinder Parshad, Vurthaluru Seenu, Sandeep R. Mathur, Smriti Hari and Naranamangalam R. Jagannathan 197 Clinical Breast MR Using MRS or DWI: Who Is the Winner? Francesco Sardanelli, Luca Alessandro Carbonaro, Stefania Montemezzi, Carlo Cavedon and Rubina Manuela Trimboli Ovarian Cancer 205 Choline Metabolism Alteration: A Focus on Ovarian Cancer Marina Bagnoli, Anna Granata, Roberta Nicoletti, Balaji Krishnamachary, Zaver M. Bhujwalla, Rossella Canese, Franca Podo, Silvana Canevari, Egidio Iorio and Delia Mezzanzanica 212 In vivo Magnetic Resonance Metabolic and Morphofunctional Fingerprints in Experimental Models of Human Ovarian Cancer Rossella Canese, Delia Mezzanzanica, Marina Bagnoli, Stefano Indraccolo, Silvana Canevari, Franca Podo and Egidio Iorio 219 Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism Marie-France Penet, Balaji Krishnamachary, Flonne Wildes, Yelena Mironchik, Delia Mezzanzanica, Franca Podo, Max de Reggi, Bouchra Gharib and Zaver M. Bhujwalla 5 Frontiers in Oncology July 2017 | Exploring Cancer Metabolic Reprogramming Prostate Cancer 228 Tissue Microstructure Is Linked to MRI Parameters and Metabolite Levels in Prostate Cancer Kirsten Margrete Selnæs, Riyas Vettukattil, Helena Bertilsson, Alan J. Wright, Arend Heerschap, Anders Angelsen, May-Britt Tessem and Tone Frost Bathen 235 Metabolic Imaging in Prostate Cancer: Where We Are Claudia Testa, Cristian Pultrone, David Neil Manners, Riccardo Schiavina and Raffaele Lodi 6 Frontiers in Oncology July 2017 | Exploring Cancer Metabolic Reprogramming April 2017 | Volume 7 | Article 79 7 Editorial published: 26 April 2017 doi: 10.3389/fonc.2017.00079 Frontiers in Oncology | www.frontiersin.org Edited by: Giuseppe Esposito, MedStar Georgetown University Hospital, USA Reviewed by: Giuseppe Esposito, MedStar Georgetown University Hospital, USA Deborah K. Hill, Norwegian University of Science and Technology (NTNU), Norway Santosh Kumar Bharti, Johns Hopkins School of Medicine, USA *Correspondence: Franca Podo franca.podo@alice.it, franca.podo@iss.it Specialty section: This article was submitted to Cancer Imaging and Diagnosis, a section of the journal Frontiers in Oncology Received: 03 January 2017 Accepted: 11 April 2017 Published: 26 April 2017 Citation: Podo F, Bhujwalla ZM and Iorio E (2017) Editorial: Exploring Cancer Metabolic Reprogramming through Molecular Imaging. Front. Oncol. 7:79. doi: 10.3389/fonc.2017.00079 Editorial: Exploring Cancer Metabolic reprogramming through Molecular imaging Franca Podo 1 *, Zaver M. Bhujwalla 2 and Egidio Iorio 1 1 Istituto Superiore di Sanità, Rome, Italy, 2 The Johns Hopkins University School of Medicine, Baltimore, MD, USA Keywords: editorial, energy metabolism, cancer metabolic reprogramming, molecular imaging, imaging methods Editorial on the Research Topic Exploring Cancer Metabolic Reprogramming through Molecular Imaging BaCKGroUNd aNd PUrPoSE oF tHE toPiC Oncogene-driven reprogramming of energy metabolism has been added in 2011 to the list of general cancer hallmarks originally introduced by Hanahan and Weinberg to rationalize the complexities of neoplastic diseases (1, 2). However, a growing body of evidence points today to the more gen- eral vision of a wider cancer metabolic reprogramming not restricted to the deregulated cellular bioenergetics linked to aerobic glycolysis (Warburg effect), but encompassing a more complex network of concerted biochemical reactions. This wider metabolic network is responsible for the redirection of carbon and phosphorus fluxes through pathways involved in nucleotide, neutral lipid, and phospholipid biosynthesis, as well as in the oncogene-driven production of second messengers essential to cell growth and tumor invasiveness in a hostile tumor environment. Multiple efforts addressed to elucidate the key mechanisms of this more comprehensive metabolic rewiring recently led to the identification of novel signatures of malignancy, thus providing the grounds for improving cancer diagnosis and monitoring tumor response to therapy using advanced molecular imaging approaches. Among these, magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging, positron emission tomography (PET), functional MR imaging, and optical imaging technologies, combined with latest-generation cellular imaging approaches, currently offer powerful means to explore and monitor the effects of cancer metabolic reprogramming, a most versatile molecular machinery to counteract the effects of the microenvironment and eventually resist the attack of anticancer treatments. The progress of high-tech engineering and molecular imaging methods, combined with genomic, proteomic, and phosphor-proteomic approaches, are progressively improving the effectiveness of image-based clinical examinations and provide the basis to design and preclinically evaluate new targeted anticancer therapies. The present research topic focuses on current achievements, challenges, and needs in the applica- tion of molecular imaging methods to explore different aspects of cancer metabolic reprogramming, with the final goal of improving individualized therapeutic decisions and patient outcome. Major attention has been focused on the links among oncogene-driven metabolic reprogramming, tumor progression, and response to therapy, as well as on the evolving capabilities of metabolic imaging technologies in cancer diagnosis, staging, and therapy monitoring (see Scheme 1 ). The topic hosted 22 scientific contributions covering in a concerted manner these cutting-edge and cross-fertilizing research fields, including three general reviews, one opinion article, one per- spective article, eight minireviews, and nine original articles, together with a combined list of over 90 keywords in oncology and metabolic imaging. 8 Podo et al. Imaging Cancer Metabolic Reprogramming Frontiers in Oncology | www.frontiersin.org April 2017 | Volume 7 | Article 79 EXPloriNG tHE liNKS oF CaNCEr MEtaBoliC rEProGraMMiNG WitH tUMor ProGrESSioN aNd rESPoNSE to tHEraPY USiNG MolECUlar iMaGiNG aPProaCHES: PrESENt ViEWS aNd PErSPECtiVES As noted in the opinion article by Serrao and Brindle, clini- cal oncology relies increasingly on biomedical imaging, with anatomical imaging, especially computed tomography (CT) and MRI, forming the mainstay of patient assessment, from diagnosis to treatment monitoring. However, the need for further improvements in specificity and sensitivity, coupled with imaging techniques that are reaching their limit of clinically attainable spatial resolution, has resulted in the emergence and growing use of imaging techniques with additional functional read-outs, such as 2-deoxy-2[ 18 F]fluoro-d-glucose ( 18 FDG)-PET and mul- tiparametric MRI. These techniques add a new dimension to our understanding of the biological behavior of tumors, allowing a more personalized approach to patient management. Compared to normal differentiated cells, cancer cells require a metabolic reprogramming to support their high proliferation rates and survival. A rewiring of energy metabolism through the Warburg effect is essential to generate the required biomass, including membrane biosynthesis, and to overcome bioenergetic and redox stress. Both established and evolving radioprobes developed in association with PET to detect tumor cell metabo- lism, and effects of treatment have been reviewed by Challapalli and Aboagye. In addition to providing us with opportunities for examining the complex regulation of reprogrammed energy metabolism in living subjects, the PET methods open up oppor- tunities for monitoring pharmacological activity of new therapies that directly or indirectly inhibit tumor cell metabolism. 1 H-MRS measurements have also been used to investigate tumor metabolism for diagnostic purposes. However, clinical applications of MRS have been hampered by low sensitivity and consequently low spatial and temporal resolution. Nuclear spin hyperpolarization of 13 C-labeled substrates by dynamic nuclear polarization (DNP) radically increases the sensitivity of these substrates to detection by 13 C MRS (3). DNP has rejuvenated inter- est in MRS measurements of tissue metabolism, as overviewed by Serrao and Brindle, with a focus on the potential clinical role for metabolic imaging with hyperpolarized [1- 13 C]pyruvate. Successful translation of this technique to the clinic was achieved recently with measurements of [1- 13 C]pyruvate metabolism in prostate cancer (4). An original research article by Glickson and colleagues (Shestov et al.) on 13 C MRS and LC-MS flux analysis of tumor intermediary metabolism presented the first validated metabolic network model for analysis of flux through key pathways of tumor intermediary metabolism including glycolysis, the oxidative and non-oxidative arms of the pentose pyrophosphate shunt, and the TCA cycle, as well as its anaplerotic pathways, pyruvate malate shuttling, glutaminolysis, and fatty acid biosynthesis and oxida- tion. Two models, respectively called bonded cumomer analysis for application to 13 C MRS data and fragmented cumomer analy- sis for mass spectrometric data, are refined and efficient forms of isotopomer analysis that can be readily expanded to incorporate glycogen, phospholipid and other pathways, thereby encompass- ing all the key pathways of tumor intermediary metabolism. Results validated with melanoma and lymphoma cell models suggest the potential translation of these methods to in situ investigations on human cancer reprogramming using MRS with stable 13 C isotopically labeled substrates on instruments operat- ing at high magnetic fields ( ≥ 7 T), possibly in combination with FDG-PET and hyperpolarized 13 C MRS methods. Mutations in metabolic enzymes involved in cell bioenergetics but not directly responsible for aerobic glycolysis may also play an important role in cancer metabolic reprogramming. Notably, mutations in the metabolic enzyme isocitrate dehydrogenase (IDH), whose wild-type form catalyzes the interconversion of isocitrate to α -ketoglutarate, have recently been identified as drivers in the development of several tumor types. In particular, cytosolic IDH1 is mutated in 70–90% of low-grade gliomas and secondary glioblastomas, and mitochondrial IDH2 is mutated in about 20% of acute myeloid leukemia cases. An article by Ronen and colleagues (Viswanath et al.) provides a timely overview of the metabolic changes observed in mutant IDH cells and the various molecular imaging methods that have been used to characterize these changes. The review describes how metabolic imaging has helped shed light on the basic biology of mutant IDH cells and how this information can be leveraged to identify new therapeutic targets and develop new clinically translatable imaging methods to detect and monitor mutant IDH tumors in vivo As reviewed by Glunde and colleagues (Cheng et al.), recent evidence suggests that cancer cells undergo metabolic reprogram- ming beyond aerobic glycolysis and bioenergetic rewiring, in the course of tumor development and progression. Starting from pio- neering studies at the end of the last century (5–7), a progressive awareness has been built on the impact of the MRS-detectable aberrant tumor phospholipid metabolism on oncogene-driven cell signaling perturbations, which lead to altered cell proliferation and block of cell differentiation (8, 9). In this context, all cancers tested so far display abnormal choline and ethanolamine phos- pholipid metabolism, which has been detected with numerous MRS approaches in cells, animal models of cancer, and the tumors SCHEME 1 | overview of research topic. 9 Podo et al. Imaging Cancer Metabolic Reprogramming Frontiers in Oncology | www.frontiersin.org April 2017 | Volume 7 | Article 79 of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, recently also ethanolamine, and phospholipid metabo- lism [including choline kinase alpha (ChK α ), phospholipase D1, phosphatidylcholine-specific phospholipase C (PC-PLC), sphin- gomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N -methyltransferase, and ethanola- mine kinase] have been shown to be involved in carcinogenesis and tumor progression, suggesting their potential use as targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. Besides aerobic glycolysis and altered choline metabolism, tumors are often characterized by peculiar microenvironment features such as hypoxia, vascular abnormalities, and low extra- cellular pH (pHe). The impact of these tumor characteristics has been investigated extensively in the context of tumor development, progression, and treatment response, resulting in a number of non- invasive imaging biomarkers. As highlighted by Ramamonjisoa and Ackerstaff, additional emerging evidence reveals that the inter- action between tumor and stroma cells can alter tumor metabolism (leading to metabolic reprogramming) as well as tumor growth and vascular features. The review summarizes the current efforts to clarify how non-invasive multimodal imaging can help to char- acterize tumor–stroma interaction and understand its role in the development, progression, and treatment response of tumors. The potential of induced metabolic bioluminescence imaging (imBI) to uncover metabolic effects of antiangiogenic therapy in tumors has been overviewed by Indraccolo and Mueller-Klieser. Tumor heterogeneity at the genetic level has been illustrated by a multitude of studies on the genomics of cancer, but whether tumors can be heterogeneous at the metabolic level is an issue that has been less systematically investigated so far. A burning related question is whether the metabolic features of tumors can change following either natural tumor progression (i.e., in primary tumors versus metastasis) or therapeutic interventions. In this regard, recent findings by independent teams indicate that antiangiogenic drugs cause metabolic perturbations in tumors, as well as metabolic adaptations associated with increased malignancy. ImBI is an imaging technique that enables detection of key metabolites associated with glycolysis, including lactate, glucose, pyruvate, and ATP in tumor sections. Signals captured by imBI can be used to visualize the topographic distribution of these metabolites and quantify their absolute amount. ImBI can be very useful for metabolic classification of tumors and to track metabolic changes in the glycolytic pathway associated with certain therapies. Imaging of the metabolic changes induced by antiangiogenic drugs in tumors by imBI or other emerging tech- nologies is a valuable tool to uncover molecular sensors engaged by metabolic stress and offers an opportunity to understand how metabolism-based approaches could improve cancer therapy. A perspective article by Podo and colleagues entitled “Activation of phosphatidylcholine-specific phospholipase C in breast and ovarian cancer: impact on MRS-detected choline metabolic profile and perspectives for targeted therapy” (Podo et al.) provides an overview of recent findings on functional and metabolic features of PC-PLC in breast and ovarian cancer cells in terms of (a) activation, protein overexpression, and subcellular redistribution of this enzyme in cancer cells compared with non- tumoral counterparts; (b) relative contributions of ChK α and PC-PLC to the intracellular MRS-detected phosphocholine pool; (c) interaction of PC-PLC with ErbB receptors’ family members such as human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 1 (HER1, EGFR); and (d) effects of PC-PLC inhibition on HER2 overexpression, cell proliferation, and cell differentiation (10, 11). This body of evi- dence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically moni- tored by molecular imaging methods. The unique capabilities of metabolic imaging to assess treat- ment response to cytotoxic and cytostatic agents were reviewed by Serkova and Eckhardt. For several decades, cytotoxic chemothera- peutic agents were considered the basis of anticancer treatment for patients with metastatic tumors. A decrease in tumor burden, assessed by volumetric CT and MRI, according to the Response Evaluation Criteria in Solid Tumors (RECIST), was considered as a radiological response to cytotoxic chemotherapies. In addition to RECIST-based dimensional measurements, a metabolic response to cytotoxic drugs can be assessed by PET using 18 F-fluoro- thymidine ( 18 FLT) as a radioactive tracer for drug-disrupted DNA synthesis. The decreased 18 FLT-PET uptake is often seen concur- rently with increased apparent diffusion coefficients by diffusion- weighted MRI (DWI) due to chemotherapy-induced changes in tumor cellularity. Recently, the discovery of molecular origins of tumorigenesis led to the introduction of novel signal transduction inhibitors (STIs). STIs are targeted cytostatic agents; their effect is based on a specific biological inhibition with no immediate cell death. As such, tumor size is no longer a sensitive end point for a treatment response to STIs; novel physiological imaging end points are needed. For receptor tyrosine kinase inhibitors, as well as modulators of the downstream signaling pathways, an almost immediate inhibition in glycolytic activity (the Warburg effect) and phospholipid turnover (the Kennedy pathway) has been seen by metabolic imaging in the first 24 h of treatment. The quantita- tive imaging end points by MRS and metabolic PET (including 18 FDG and total choline) provide an early treatment response to targeted STIs, before a reduction in tumor burden can be seen. CHallENGES aNd FUtUrE dirECtioNS iN tHE aPPliCatioN oF MEtaBoliC iMaGiNG aPProaCHES to PrECliNiCal ModElS aNd to CaNCEr PatiENtS A series of 13 original articles or minireviews focused on MRI and metabolic imaging studies on cell-based models, dissected tissue specimens, and in vivo tissues especially in breast (Pais and Degani; Iorio et al.; Mori et al.; Haukaas et al.; Palma et al.; van der Kemp et al.; Sharma et al.; Sardanelli et al.), ovarian (Bagnoli et al.; Canese et al.; Penet et al.), and prostate cancers (Mori et al.; Selnaes et al.; Testa et al.). 10 Podo et al. Imaging Cancer Metabolic Reprogramming Frontiers in Oncology | www.frontiersin.org April 2017 | Volume 7 | Article 79 The reported studies on breast cancer highlight relevant issues concerning development of quantitative molecular imaging methods that specifically detect estrogen receptor (ER) in vivo using novel ER-targeted contrast agents (Pais and Degani); iden- tification of key players in choline metabolic reprogramming in triple negative breast cancer (Iorio et al.); influence of the tumor microenvironment on choline and lipid metabolism (Mori et al.); impact of freezing delay time on tissue samples for metabolomic studies (Haukaas et al.); monitoring of metabolic changes induced by gamma irradiation on breast tumor spheroids using 1 H NMR spectroscopy and microimaging (Palma et al.); identification of 31 P MRS phosphodiester signals of human fibroglandular breast tissue at ultrahigh field (van der Kemp et al.); and evaluation of the potential of DWI in the characterization of malignant, benign, and healthy breast tissues and molecular subtypes of breast can- cer (Sharma et al.). An article entitled “Clinical breast MR using MRS or DWI: Who is the winner?” by Sardanelli et al. provides a critical summary of secondary evidence on two different in vivo non-contrast molecular imaging approaches, 1 H MRS and DWI, with special focus on the translational perspective toward clinical feasibility and applicability. Regarding epithelial ovarian carcinoma (EOC), a highly heterogeneous and lethal malignancy characterized by late diagnosis, frequent relapse, and development of chemoresistance, Bagnoli and colleagues reviewed the role of ChK α in sustaining the cancer “cholinic phenotype” (Bagnoli et al. ). The article shows that ChK α inhibition, besides reducing ovarian cancer aggressiveness, increases disease sensitivity to drug treatment sparing normal cells and therefore opening a new therapeutic window. An abnormal tCho profile along with altered levels of other metabolites has also been detected in human EOC xeno- grafts, as reviewed by Canese and colleagues (Canese et al.). This molecular imaging study provides a more extensive picture of tumor metabolism in EOC models in vivo , potentially opening the way to a multiple metabolic targeting. Furthermore, DWI is suggested as a potential tool for better differentiating malignant from benign tissues and possibly distinguishing cytotoxic from cytostatic treatment effects. New therapeutic strategies are urgently needed to improve survival of ovarian cancer patients. The effect of pantethine (precursor of vitamin B5 and active moi- ety of coenzyme A) on ovarian tumor progression and choline metabolism has been investigated by (Penet et al.) using MRI and high-resolution 1 H MRS in a orthotopic ovarian cancer model. Pantethine treatment resulted in slower tumor progression, decreased levels of phosphocholine and phosphatidylcholine, and reduced metastases and ascites occurrence. MRI can portray spatial variations in tumor heterogeneity, architecture, and tumor microenvironment, key biological features of prostate cancer. An original research article by Selnaes et al. focused on the relationships between MRI param- eters measured on prostate cancer patients in vivo , individual metabolites measured ex vivo in prostatectomy specimens, and quantitative histopathology (Selnaes et al.). Last, but not least, Testa and colleagues reviewed the recent literature regarding molecular imaging methods developed and used to improve diagnosis and staging of prostate cancer (Testa et al. ). The encouraging progress of in vivo metabolic imaging approaches nowadays points to the need of harmonized and shared protocols to increase the applicability of these technologies to a clinical setting. 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Diffusion- weighted MRI for early detection and characterization of prostate cancer in the transgenic adenocarcinoma of the mouse prostate model J Magn Reson Imaging (2016) 43:1207–17. doi:10.1002/jmri.25087 Conflict of Interest Statement: The authors declare that the research was con- ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, SB, declared a shared affiliation and a past coauthorship with one of the authors, ZB, to the handling editor, who ensured that the process nevertheless met the standards of a fair and objective review. Copyright © 2017 Podo, Bhujwalla and Iorio. This is an open-access article distrib- uted under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. March 2016 | Volume 6 | Article 59 11 OpiniOn published: 11 March 2016 doi: 10.3389/fonc.2016.00059 Frontiers in Oncology | www.frontiersin.org Edited by: Franca Podo, Istituto Superiore di Sanitá, Italy Reviewed by: Natalie Julie Serkova, University of Colorado, USA Sarah Nelson, University of California San Francisco, USA *Correspondence: Kevin M. Brindle kmb1001@cam.ac.uk Specialty section: This article was submitted to Cancer Imaging and Diagnosis, a section of the journal Frontiers in Oncology Received: 23 December 2015 Accepted: 28 February 2016 Published: 11 March 2016 Citation: Serrao EM and Brindle KM (2016) Potential Clinical Roles for Metabolic Imaging with Hyperpolarized [1- 13 C]Pyruvate. Front. Oncol. 6:59. doi: 10.3389/fonc.2016.00059 potential Clinical Roles for Metabolic imaging with Hyperpolarized [1- 13 C]pyruvate Eva M. Serrao 1,2 and Kevin M. Brindle 1,2 * 1 Li Ka Shing Centre, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK, 2 Department of Biochemistry, University of Cambridge, Cambridge, UK Keywords: cancer, metabolism, imaging, hyperpolarized, pyruvate, therapy monitoring Clinical oncology relies increasingly on biomedical imaging, with anatomical imaging, especially using CT and 1 H-MRI, forming the mainstay of patient assessment, from diagnosis to treatment monitoring. However, the need for further improvements in specificity and sensitivity, coupled with imaging techniques that are reaching their limit of clinically attainable spatial resolution, has resulted in the emergence and growing use of imaging techniques with additional functional readouts, such as 18 FDG-PET and multiparametric MRI. These techniques add a new dimension to our understanding of the biological behavior of tumors, allowing a more personalized approach to patient management. An important functional imaging target in cancer is metabolism. PET measurements of 18 Fluorodeoxyglucose uptake ( 18 FDG-PET), a 18 F-labeled glucose analog, and 1 H-MRS measure- ments, have both been used to investigate tumor metabolism for diagnostic purposes. However, clinical applications of MRS have been hampered by low sensitivity and consequently low spatial and temporal resolution (1). Nuclear spin hyperpol