Wnt Pathway cancer metabolism is a valuable approach for PD biomarker discovery

Histone deacetylase inhibitors are currently approved for cutaneous T cell Wnt Pathway lymphoma and are in midlate stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy . In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by 1H and 31P MRS in prostate and colon carcinoma cells. In addition, 1H MRSshowed an increase in branched chain amino acid and alanine concentrations. 13C choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase a expression.
Furthermore, metabolic labeling experiments with 13C glucose showed that differential glucose Imiquimod routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in the choline/water and phosphomonoester /total phosphate ratios in vivo. Together, our findings provide mechanistic insights into the impact of HDAC inhibition on cancer cell metabolism and highlight PC as a candidate noninvasive imaging biomarker for monitoring the action of HDAC inhibitors. Histone acetylation is a key regulator of eukaryotic gene expression which controls DNA accessibility to transcription factors and mRNA transcription. The histone acetylation/ deacetylation balance is maintained by the opposing activities of histone acetyl transferases and histone deacetylases resulting in cell specific gene expression patterns .
Deregulation of histone acetylation results in abnormal gene expression profiles involved in controlling cell proliferation, differentiation and apoptosis, and is associated with malignancy .HDACs also act on other nonhistone proteins that are subject to regulation by acetylation including some transcription factors and the heat shock farriers protein 90 molecular chaperone, which maintains the conformational stability of several oncogenic proteins . HDAC inhibition is a promising antitumor approach for simultaneously targeting multiple oncogenic players and pathways. SeveralHDACinhibitors have been described that induce potent antitumor effects in cells and tumor xenografts . The HDAC inhibitors SAHA and depsipeptide FK228 have gained U.S.
Food and Drug Administration approval for cutaneous T cell lymphoma treatment and many more are currently under clinical evaluation . One example is belinostat which has shown promising activity in preclinical cancer models and in patients . The development and evaluation of novel HDAC inhibitors require the identification and validation of pharmacodynamic biomarkers of drug activity. These are important because they inform on the inhibition of the intended biochemical target, help assess response dynamics, aid treatment schedule and dose planning, and subsequently allow therapeutic efficacy assessment . In contemporary drug development, noninvasive endpoints of target modulation are highly desirable as they do not involve surgical intervention and allow longitudinal studies in the same patient to be carried out . Noninvasive imaging of cancer metabolism is a valuable approach for PD biomarker discovery.

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