Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations

The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since IDH mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in IDH lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to R-2-hydroxyglutarate (R-2-HG). It is proposed that elevated cellular R-2-HG inhibits enzymes that regulate transcription and metabolism, subsequently affecting nuclear, cytoplasmic, and mitochondrial biochemistry. The significance of these biochemical changes for tumorigenesis and potential for therapeutic exploitation remains unclear. Here we comprehensively review reported direct and indirect metabolic changes linked to IDH mutations and discuss their clinical significance. We also review the metabolic effects of first-generation mutant IDH inhibitors and highlight the potential for combination treatment strategies and new metabolic targets

³¹P magnetization transfer magnetic resonance spectroscopy: assessing the activation induced change in cerebral ATP metabolic rates at 3 T

Purpose: In vivo ³¹P MRS magnetization transfer (MT) provides a direct measure of neuronal activity at the metabolic level. This work aims to use functional ³¹P MRS-MT to investigate the change in cerebral ATP metabolic rates in healthy adults upon repeated visual stimuli. Methods: A magnetization saturation transfer sequence with narrowband selective saturation of γ-ATP was developed for ³¹P MT experiments at 3 T. Results: Using progressive saturation of γ-ATP, the intrinsic T1 relaxation times of phosphocreatine (PCr) and inorganic phosphate (Pi) at 3 T were measured to be 5.1±0.8 s and 3.0±1.4 s, respectively. Using steady-state saturation of γ-ATP, a significant 24±14% and 11±7% increase in the forward creatine kinase (CK) pseudo-first-order reaction rate constant, k₁, was observed upon visual stimulation in the first and second cycles respectively of a paradigm consisting of 10min-rest followed by 10min-stimulation, with the measured baseline k₁ being 0.35±0.04 s⁻¹. No significant changes in forward ATP synthase (ATPase) reaction rate, PCr/γ- ATP, Pi/γ-ATP, and NAD(H)/γ-ATP ratios, or intracellular pH were detected upon stimulation. Conclusion: This work demonstrates the potential of studying cerebral bioenergetics using functional ³¹P MRS-MT to determine the change in the forward CK reaction rate at 3 T

Nervous system metabolism

The aim of this thesis was to investigate the cellular biochemistry and metabolism of the human brain in vivo using magnetic resonance as the basic technique. Magnetic resonance imaging (MRI) can provide images of human structure and has already proved to be diagnostically useful in Neurology. Magnetic resonance spectroscopy (MRS) has the potential for measuring the tissue metabolite concentrations and metabolic rates of intracellular reactions in vivo. The great advantage of MRS is that many elements already present in abundance can be used to follow these intracellular reactions; no alien compounds need to be injected into the subject in the hope that they will eventually enter the tissue under investigation. However there are still considerable problems in receiving signal from the region of interest. No single approach in MRS has proved to be suitable for all investigations. An existing technique in MRS, phase modulated rotating frame imaging (PMRFI) was extended to measure absolute tissue concentration and enzyme flux rates of intracellular compounds containing phosphorus nuclei at above 1mmol/L tissue concentration in tissue volumes greater than 10ml. These technical limitations restricted the work of this thesis to the human cerebral hemispheres. Adenosine triphosphate (ATP) and phosphocreatine (PCr) are essential cytoplasmic compounds, providing energy for transport and biosynthetic pathways within the cell. Phosphorus MRS can also measure intracellular pH (pHi), providing an insight into ion metabolism within the cell. Finally 31P MRS can also measure the concentration of certain phospholipid groups and their precursors, phosphoethanolamine (PE) and phosphocholine (PC). The initial work carried out involved the construction, testing and modification of a probe suitable for clinical work. Studies were performed on subjects to establish a normal range for absolute tissue concentrations and enzyme flux rates through creatine phosphokinase. Studies on patients with primary brain tumours, acromegaly, herpes simplex encephalitis, HIV infections and those recovering following severe head injury were studied. Consistent changes in pHi, high energy phosphate and phospholipid metabolism were found in these conditions. The probable mechanisms underlying these changes are discussed and further investigations suggested.</p

Nervous system metabolism: a magnetic resonance study

The aim of this thesis was to investigate the cellular biochemistry and metabolism of the human brain in vivo using magnetic resonance as the basic technique. Magnetic resonance imaging (MRI) can provide images of human structure and has already proved to be diagnostically useful in Neurology. Magnetic resonance spectroscopy (MRS) has the potential for measuring the tissue metabolite concentrations and metabolic rates of intracellular reactions in vivo. The great advantage of MRS is that many elements already present in abundance can be used to follow these intracellular reactions; no alien compounds need to be injected into the subject in the hope that they will eventually enter the tissue under investigation. However there are still considerable problems in receiving signal from the region of interest. No single approach in MRS has proved to be suitable for all investigations. An existing technique in MRS, phase modulated rotating frame imaging (PMRFI) was extended to measure absolute tissue concentration and enzyme flux rates of intracellular compounds containing phosphorus nuclei at above 1mmol/L tissue concentration in tissue volumes greater than 10ml. These technical limitations restricted the work of this thesis to the human cerebral hemispheres. Adenosine triphosphate (ATP) and phosphocreatine (PCr) are essential cytoplasmic compounds, providing energy for transport and biosynthetic pathways within the cell. Phosphorus MRS can also measure intracellular pH (pHi), providing an insight into ion metabolism within the cell. Finally 31P MRS can also measure the concentration of certain phospholipid groups and their precursors, phosphoethanolamine (PE) and phosphocholine (PC). The initial work carried out involved the construction, testing and modification of a probe suitable for clinical work. Studies were performed on subjects to establish a normal range for absolute tissue concentrations and enzyme flux rates through creatine phosphokinase. Studies on patients with primary brain tumours, acromegaly, herpes simplex encephalitis, HIV infections and those recovering following severe head injury were studied. Consistent changes in pHi, high energy phosphate and phospholipid metabolism were found in these conditions. The probable mechanisms underlying these changes are discussed and further investigations suggested

Isocitrate dehydrogenase gene variants in cancer and their clinical significance

Human isocitrate dehydrogenase (IDH) genes encode for the IDH1, 2 & 3 isoenzymes which catalyse the formation of 2-oxoglutarate from isocitrate and are essential for normal mammalian metabolism. Although mutations in these genes in cancer were long thought to lead to a ‘loss of function’, combined genomic and metabolomic studies led to the discovery that a common IDH 1 mutation, present in low-grade glioma and acute myeloid leukaemia (AML), yields a variant (R132H) with a striking change of function leading to the production of (2R)-hydroxyglutarate (2HG) which consequently accumulates in large quantities both within and outside cells. Elevated 2HG is proposed to promote tumorigenesis, although the precise mechanism by which it does this remains uncertain. Inhibitors of R132H IDH1, and other subsequently identified cancer-linked 2HG producing IDH variants, are approved for clinical use in the treatment of chemotherapy-resistant AML, though resistance enabled by additional substitutions has emerged. In this review, we provide a current overview of cancer linked IDH mutations focussing on their distribution in different cancer types, the effects of substitution mutations on enzyme activity, the mode of action of recently developed inhibitors, and their relationship with emerging resistance-mediating double mutations

Isocitrate dehydrogenase gene variants in cancer and their clinical significance

Human isocitrate dehydrogenase (IDH) genes encode for the IDH1, 2 & 3 isoenzymes which catalyse the formation of 2-oxoglutarate from isocitrate and are essential for normal mammalian metabolism. Although mutations in these genes in cancer were long thought to lead to a ‘loss of function’, combined genomic and metabolomic studies led to the discovery that a common IDH 1 mutation, present in low-grade glioma and acute myeloid leukaemia (AML), yields a variant (R132H) with a striking change of function leading to the production of (2R)-hydroxyglutarate (2HG) which consequently accumulates in large quantities both within and outside cells. Elevated 2HG is proposed to promote tumorigenesis, although the precise mechanism by which it does this remains uncertain. Inhibitors of R132H IDH1, and other subsequently identified cancer-linked 2HG producing IDH variants, are approved for clinical use in the treatment of chemotherapy-resistant AML, though resistance enabled by additional substitutions has emerged. In this review, we provide a current overview of cancer linked IDH mutations focussing on their distribution in different cancer types, the effects of substitution mutations on enzyme activity, the mode of action of recently developed inhibitors, and their relationship with emerging resistance-mediating double mutations

Isocitrate dehydrogenase variants in cancer — Cellular consequences and therapeutic opportunities

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP+ ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG). Elevated d-2HG is a biomarker for some cancers, and inhibition of IDH1 and IDH2 variants is being pursued as a medicinal chemistry target. We provide an overview of the types of cancer-associated IDH variants, discuss some of the proposed consequences of altered metabolism as a result of elevated d-2HG, summarise therapeutic efforts targeting IDH variants and identify areas for future research

Acute vasospasm following transcallosal resection of a xanthogranulomatous colloid cyst of the 3rd ventricle.

We present the first case of a 57 year old man who developed severe, acute vasospasm following transcallosal resection of an unusual, xanthogranulomatous colloid cyst. The 16 year history of growth of this cyst may have resulted in its unusual pathology, and the subsequent vasospastic reaction to its excision. We discuss the potential pathological relationship between the inflammatory nature of the cyst, chemical meningitis and vasospasm, and what this implies about vasospasm in general. The severe, life-threatening vasospasm affected all four major vessels and required aggressive management by endovascular injection of nimodipine and angioplasty, with good recovery. The case illustrates a previously undescribed sequel of surgery for this condition, demonstrates an effective treatment and offers possible insights into the pathogenesis of vasospasm