Understanding the Intersections between Metabolism and Cancer Biology

Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers

The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner-Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch. The oxidative branch is highly active in most eukaryotes and converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate and NADPH. The latter function is critical to maintain redox balance under stress situations, when cells proliferate rapidly, in ageing, and for the 'Warburg effect' of cancer cells. The non-oxidative branch instead is virtually ubiquitous, and metabolizes the glycolytic intermediates fructose 6-phosphate and glyceraldehyde 3-phosphate as well as sedoheptulose sugars, yielding ribose 5-phosphate for the synthesis of nucleic acids and sugar phosphate precursors for the synthesis of amino acids. Whereas the oxidative PPP is considered unidirectional, the non-oxidative branch can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand. These functions require dynamic regulation of the PPP pathway that is achieved through hierarchical interactions between transcriptome, proteome and metabolome. Consequently, the biochemistry and regulation of this pathway, while still unresolved in many cases, are archetypal for the dynamics of the metabolic network of the cell. In this comprehensive article we review seminal work that led to the discovery and description of the pathway that date back now for 80 years, and address recent results about genetic and metabolic mechanisms that regulate its activity. These biochemical principles are discussed in the context of PPP deficiencies causing metabolic disease and the role of this pathway in biotechnology, bacterial and parasite infections, neurons, stem cell potency and cancer metabolism.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/brv.12140

The return of metabolism: biochemistry and physiology of the pentose phosphate pathway

Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.

Metabolic reprogramming and cancer progression

Lactate Metabolism in Human Lung Tumors

This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

/pdf/metabolic-imaging-of-patients-with-prostate-cancer-using-3qnu09y4ny.pdf

Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate

The present invention is, in one aspect, an imaging system having a detector that has multiple detector cells extending along a z-axis, the detector being configured to collect multiple slices of data; and a scalable data acquisition system configured to convert signals from the detector to digital form, the scalable data acquisition system having a plurality of converter boards each with a plurality of channels, the channels and detector cells having an interweaved coupling to reduce susceptibility to band artifact.

Scalable multislice imaging system

A scalable data acquisition system (SDAS) that may be used in connection with both single slice and multislice imaging systems is described. Generally, the SDAS in configured for use in a computed tomography system and converts the low level electrical current signal from the x-ray detector to digital values for image reconstruction, display and archive. The SDAS also includes an anti-alias filter for each cell prior to analog to digital conversion (ADC). More specifically, the analog current signals from the detector are supplied to the SDAS input channels via shielded ribbon or flex cables. The cables are connected to the SDAS at the SDAS backplane. The SDAS Converter boards are also plugged into the SDAS backplane. This interconnection provides several advantages. For example, the backplane enables ganging the detector cells on the outside edges of the fan beam. The backplane also allows a redistribution of the detector cells to appropriate converter boards. Signals from more than one slice are contained in the same flex cable, and each converter board only serves one slice since the reconfiguration of SDAS from one multi-slice configuration to another or to the single slice configuration requires only the removal or addition of converter boards. Also, the backplane enables a blending or weaving of SDAS channels and detector cells near the end channels of a converter board. Artifacts such as a band in the image are usually the result of common or uniform error source across one group of adjacent channels versus a neighboring group of channels. If all the channels on one converter board have a common error difference compared to a neighboring converter board, this type of image artifact is quite likely. By interweaving detector cell assignments versus converter card on the edges of the converter card, the susceptibility to a band artifact is reduced.

Scalable data acquisition system

A PET scanner contains a positron emission event qualifier which prevents noise from being misinterpreted as such an event. A radiation detector signal indicates the intensity and duration of sensed gamma radiation. A comparator produces an intermediate signal when the radiation detector signal exceeds a predetermined threshold. A delay line delays the intermediate signal by an interval of time and blocks any pulses in the intermediate signal which are shorter than this interval. Typical noise in the intermediate signal is shorter in duration than this interval of time.

Radiation event qualifier for positron emission tomography

An electron paramagnetic resonance imaging (EPRI) system includes a resistive magnet driven by a power supply such as a power supply module to generate radio frequency signals in a substantially coherent polyphase perfect sequence scheme. The EPRI system further includes image acquisition and processing electronics configured to generate, acquire, quantify and map pO2 information associated with a free radical agent in vivo and having a resonance line width that is sensitive to oxygen and in response to the radio frequency signals without imparting harmful heating effects to a corresponding human or animal body.

Jonathan Alan Murray

Papers

Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate

Scalable multislice imaging system

Scalable data acquisition system

Radiation event qualifier for positron emission tomography

Electron spin resonance imaging scanner