PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2

Witney, Timothy H.; James, Michelle L.; Shen, Bin; Chang, Edwin; Pohling, Christoph; Arksey, Natasha; Hoehne, Aileen; Shuhendler, Adam J.; Park, Jun Hyung; Bodapati, Deepika; Weber, Judith; Gowrishankar, Gayatri; Rao, Jianghong; Chin, Frederick T.; Gambhir, Sanjiv S.

doi:10.1126/scitranslmed.aac6117

Cited by 60 publications

(53 citation statements)

References 39 publications

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“…PKM2 expression in tumors is the basis for a positron emission tomography (PET) imaging agent. N,N-diarylsulfonamide (DASA) compounds bind to PKM2, and an 11 C-labeled analog of DASA-23 is taken up by PKM2-expressing orthotopic gliomas in mice, providing imaging contrast with the normal brain (Witney et al, 2015). Other investigational PET agents exploit the ability of some tumors to take up and retain glutamine (Venneti et al, 2015).…”

Section: Can Cancer Metabolism Be Exploited To Improve Therapy?mentioning

confidence: 99%

Understanding the Intersections between Metabolism and Cancer Biology

Heiden

DeBerardinis

2017

Cell

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Transformed cells adapt metabolism to support tumor initiation and progression. Specific metabolic activities can participate directly in the process of transformation or support the biological processes that enable tumor growth. Exploiting cancer metabolism for clinical benefit requires defining the pathways that are limiting for cancer progression and understanding the context specificity of metabolic preferences and liabilities in malignant cells. Progress towards answering these questions is providing new insight into cancer biology and can guide the more effective targeting of metabolism to help patients.

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Section: Can Cancer Metabolism Be Exploited To Improve Therapy?mentioning

confidence: 99%

Understanding the Intersections between Metabolism and Cancer Biology

Heiden

DeBerardinis

2017

Cell

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“…As both the ability of AAV9 and DASA-23 to freely cross the BBB have been previously reported (14,25), in this study the AAV was administered to mice via stereotactic brain injection rather than IV. This is due to the high numbers of viral genome copy needed for IV administration and also to give a clearly defined region of PKM2 protein expression within the brain by PET imaging.…”

Section: Discussionmentioning

confidence: 99%

“…To date, radiolabeled DASA-23 is the only radiotracer for the PKM2 protein. It has shown great potential as an effective imaging agent in preclinical studies since it is able to cross the BBB freely and image tumors in the CNS, while having very low uptake in the brain of healthy mice as shown in biodistribution studies (12)(13)(14).…”

mentioning

confidence: 99%

Positron emission tomography reporter gene strategy for use in the central nervous system

Haywood

Beinat

Gowrishankar

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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There is a growing need for monitoring or imaging gene therapy in the central nervous system (CNS). This can be achieved with a positron emission tomography (PET) reporter gene strategy. Here we report the development of a PET reporter gene system using the PKM2 gene with its associated radiotracer [ 18 F]DASA-23. The PKM2 reporter gene was delivered to the brains of mice by adeno-associated virus (AAV9) via stereotactic injection. Serial PET imaging was carried out over 8 wk to assess PKM2 expression. After 8 wk, the brains were excised for further mRNA and protein analysis. PET imaging at 8 wk post-AAV delivery showed an increase in [ 18 F]DASA-23 brain uptake in the transduced site of mice injected with the AAV mice over all controls. We believe PKM2 shows great promise as a PET reporter gene and to date is the only example that can be used in all areas of the CNS without breaking the blood-brain barrier, to monitor gene and cell therapy.reporter gene | positron emission tomography (PET) | PKM2 | [18F]DASA-23 | adeno-associated virus

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“…Gambhir and colleagues reported the generation of a PET imaging probe specific for PKM2 using a class of N , N -diarylsulfonamides (DASA) known to promote PKM2 tetramer formation. [ 11 C] labeled DASA-23 was taken up in orthotopic glioma models and corresponded to tumor-associated PKM2 expression 38 (Figure 1). …”

Section: Glucose Metabolism: Oncogenic Reprograming and Imagingmentioning

confidence: 99%

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

et al. 2016

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The genomic revolution in cancer has uncovered a variety of mutations in primary brain tumors. This has created an urgent need to develop non-invasive imaging biomarkers to assess and integrate this genetic information in the clinical management of patients. Metabolic reprogramming is a central hallmark of cancers including brain tumors. Many of the molecular pathways implicated in brain tumors directly reprogram metabolism. This provides the opportunity to devise in vivo metabolism-based imaging modalities for patient stratification, to improve diagnosis, and to monitor treatment response. Metabolic phenomena like the Warburg effect and altered mitochondrial metabolism can be leveraged to image brain tumors using techniques like positron emission tomography (PET) imaging and Magnetic Resonance (MR) metabolic imaging. Moreover, genetic alterations such as isocitrate dehydrogenase mutations produced unique metabolic signatures that can be detected using MR spectroscopy. There is a growing need to translate our understanding of the molecular aspects of brain tumors to in vivo imaging in patients. Metabolism-based imaging provides a unique platform to achieve this. In this review we examine the molecular basis for metabolic reprograming in brain tumors and examine current non-invasive metabolic imaging strategies to interrogate them, for the ultimate goal of guiding and improving patient care.

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PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2

Cited by 60 publications

References 39 publications

Understanding the Intersections between Metabolism and Cancer Biology

Understanding the Intersections between Metabolism and Cancer Biology

Positron emission tomography reporter gene strategy for use in the central nervous system

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

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