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Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models.

ABSTRACT: Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors.

SUBMITTER: Neveu MA

PROVIDER: S-EPMC5340254 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models.

Neveu Marie-Aline MA De Preter Géraldine G Joudiou Nicolas N Bol Anne A Brender Jeffery R JR Saito Keita K Kishimoto Shun S Grégoire Vincent V Jordan Bénédicte F BF Krishna Murali C MC Feron Olivier O Gallez Bernard B

Oncotarget 20161201 49

Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induc ...[more]

PMID: 28082726

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Project description:Purpose To investigate the value of T2-weighted-based radiomics compared with qualitative assessment at T2-weighted imaging and diffusion-weighted (DW) imaging for diagnosis of clinical complete response in patients with rectal cancer after neoadjuvant chemotherapy-radiation therapy (CRT). Materials and Methods This retrospective study included 114 patients with rectal cancer who underwent magnetic resonance (MR) imaging after CRT between March 2012 and February 2016. Median age among women (47 of 114, 41%) was 55.9 years (interquartile range, 45.4-66.7 years) and median age among men (67 of 114, 59%) was 55 years (interquartile range, 48-67 years). Surgical histopathologic analysis was the reference standard for pathologic complete response (pCR). For qualitative assessment, two radiologists reached a consensus. For radiomics, one radiologist segmented the volume of interest on high-spatial-resolution T2-weighted images. A random forest classifier was trained to separate the patients by their outcomes after balancing the number of patients in each response category by using the synthetic minority oversampling technique. Statistical analysis was performed by using the Wilcoxon rank-sum test, McNemar test, and Benjamini-Hochberg method. Results Twenty-one of 114 patients (18%) achieved pCR. The radiomic classifier demonstrated an area under the curve of 0.93 (95% confidence interval [CI]: 0.87, 0.96), sensitivity of 100% (95% CI: 0.84, 1), specificity of 91% (95% CI: 0.84, 0.96), positive predictive value of 72% (95% CI: 0.53, 0.87), and negative predictive value of 100% (95% CI: 0.96, 1). The diagnostic performance of radiomics was significantly higher than was qualitative assessment at T2-weighted imaging or DW imaging alone (P < .02). The specificity and positive predictive values were significantly higher in radiomics than were at combined T2-weighted and DW imaging (P < .0001). Conclusion T2-weighted-based radiomics showed better classification performance compared with qualitative assessment at T2-weighted and DW imaging for diagnosing pCR in patients with locally advanced rectal cancer after CRT. © RSNA, 2018 Online supplemental material is available for this article.

Dataset Information

Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models.

Publications

Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models.

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