Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study

Molina, Ana Ramı́rez de; Sarmentero-Estrada, Jacinto; Belda-Iniesta, Cristóbal; Tarón, Miquel; Molina, Víctor; Cejas, Paloma; Skrzypski, Marcin; Gallego‐Ortega, David; Castro, Javier de; Casado, Enrique; García‐Cabezas, Miguel Ángel; Sánchez, José Javier; Nistal, Manuel; Rosell, Rafael; González-Barón, Manuel; Lacal, Juan Carlos

doi:10.1016/s1470-2045(07)70279-6

Cited by 139 publications

(81 citation statements)

References 27 publications

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“…Over-expression and increased ChoK activity resulting in production of PC has been detected in several human tumor derived cancer cell lines and tissue biopsies including lung, colon and prostate (9-12, 24, 25). Decreased tumor tCho is usually associated with a positive response to conventional chemotherapy in cancer and suggests a role for choline compounds as potential biomarkers to assess treatment response (26).…”

Section: Discussionmentioning

confidence: 99%

Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors

Kumar

Arlauckas

Saksena

et al. 2015

Molecular Cancer Therapeutics

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Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor progression. Increased choline is consistently observed in both pre-clinical tumor models and in human brain tumors by proton magnetic resonance spectroscopy (MRS). Thus, inhibition of choline metabolism using specific choline kinase inhibitors such as MN58b may be a promising new strategy for treatment of brain tumors. We demonstrate the efficacy of MN58b in suppressing phosphocholine production in three brain tumor cell lines. In vivo MRS studies of rats with intra-cranial F98-derived brain tumors showed a significant decrease in tumor total choline concentration after treatment with MN58b. High resolution MRS of tissue extracts confirmed that this decrease was due to a significant reduction in phosphocholine. Concomitantly, a significant increase in poly-unsaturated lipid resonances was also observed in treated tumors, indicating apoptotic cell death. Magnetic resonance imaging (MRI) based volume measurements demonstrated a significant growth arrest in the MN58b-treated tumors in comparison to saline-treated controls. Histologically, MN58b-treated tumors showed decreased cell density, as well as increased apoptotic cells. These results suggest that inhibition of choline kinase can be used as an adjuvant to chemotherapy in the treatment of brain tumors and that decreases in total choline observed by MRS can be used as an effective phamacodynamic biomarker of treatment response.

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Section: Discussionmentioning

confidence: 99%

Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors

Kumar

Arlauckas

Saksena

et al. 2015

Molecular Cancer Therapeutics

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“…By contrast, no significant correlation was found with age, tumour size, progesterone receptor status, vascular invasion and histological tumour type, or with expression of p53, ERBB2 or Ki-67, in these breast tumours 41 . These clinical findings, combined with a large body of work in cancer cells, suggest that CHKα expression and activity is directly associated with increased cancer cell proliferation and malignancy, making it a potential prognostic marker of some cancers, such as non-small-cell lung cancer 39 . CHKα expression and activity levels have not yet been investigated in metastases.…”

Section: Key Enzymes In Choline Metabolism In Cancermentioning

confidence: 99%

“…Overexpression of CHKα, but not of CHKβ, has been reported in several human tumour-derived cell lines of multiple origins, as well as in biopsy samples of lung, colon and prostate carcinomas, among others, which were compared with matched normal tissue from the same patient 34,38,39 (TABLE 1). These findings, combined with the studies in knockout mice, indicate that CHKα, but not CHKβ, is essential for PtdCho biosynthesis, which is required for the uncontrolled growth of cancer cells.…”

Section: Key Enzymes In Choline Metabolism In Cancermentioning

confidence: 99%

Choline metabolism in malignant transformation

2011

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Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

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“…ChoK phosphorylates choline that is taken up by cells through the transporters discussed earlier in the review. Both the expression and activity of ChoK have been identified to be upregulated in many cancers and are also correlated with tumor grade 32,73 . Oncogenic signaling has been implicated in the control of ChoK expression and these include the Ras and PI3K/AKT pathways, as well as its co-expression with Src family kinases and EGFR 73 .…”

Section: Tumor Metabolism By 1h Mrsmentioning

confidence: 99%

“…Both the expression and activity of ChoK have been identified to be upregulated in many cancers and are also correlated with tumor grade 32,73 . Oncogenic signaling has been implicated in the control of ChoK expression and these include the Ras and PI3K/AKT pathways, as well as its co-expression with Src family kinases and EGFR 73 . Quantification of the tCho region provides a robust and consistent marker for malignancy, with normal tissues displaying low levels of tCho while many tumors having high levels of these metabolites 74,75 .…”

Section: Tumor Metabolism By 1h Mrsmentioning

confidence: 99%

Novel Approaches to Imaging Tumor Metabolism

Tee

Keshari

2015

The Cancer Journal

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The field of metabolism research has made a dramatic resurgence in recent years, fueled by a newfound appreciation of the interactions between metabolites and phenotype. Metabolic substrates and their products can be biomarkers of a wide range of pathologies, including cancer, but our understanding of their in vivo interactions and pathways has been hindered by the robustness of non-invasive imaging approaches. The last 3 decades have been flushed with the development of new techniques for the study of metabolism in vivo. These methods include nuclear based, predominantly positron emission tomography (PET) and magnetic resonance imaging (MRI), many of which have been translated to the clinic. The purpose of this review is to introduce both long standing imaging strategies as well as novel approaches to the study of perturbed metabolic pathways in the setting of carcinogenesis. This will involve descriptions of nuclear probes labeled with 11C and 18F as well 13C for study using hyperpolarized MRI. Highlighting both advantages and disadvantages of each approach, the aim of this summary is to provide the reader with a framework for interrogation of metabolic aberrations in their system of interest.

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Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study

Cited by 139 publications

References 27 publications

Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors

Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors

Choline metabolism in malignant transformation

Novel Approaches to Imaging Tumor Metabolism

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