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- W4361244190 abstract "<div>Abstract<p>The phosphoinositide 3-kinase (PI3K) pathway is a major target for cancer drug development. PI-103 is an isoform-selective class I PI3K and mammalian target of rapamycin inhibitor. The aims of this work were as follows: first, to use magnetic resonance spectroscopy (MRS) to identify and develop a robust pharmacodynamic (PD) biomarker for target inhibition and potentially tumor response following PI3K inhibition; second, to evaluate mechanisms underlying the MRS-detected changes. Treatment of human PTEN null PC3 prostate and <i>PIK3CA</i> mutant HCT116 colon carcinoma cells with PI-103 resulted in a concentration- and time-dependent decrease in phosphocholine (PC) and total choline (tCho) levels (<i>P</i> < 0.05) detected by phosphorus (<sup>31</sup>P)- and proton (<sup>1</sup>H)-MRS. In contrast, the cytotoxic microtubule inhibitor docetaxel increased glycerophosphocholine and tCho levels in PC3 cells. PI-103–induced MRS changes were associated with alterations in the protein expression levels of regulatory enzymes involved in lipid metabolism, including choline kinase α (ChoK<sub>α</sub>), fatty acid synthase (FAS), and phosphorylated ATP-citrate lyase (pACL). However, a strong correlation (r<sup>2</sup> = 0.9, <i>P</i> = 0.009) was found only between PC concentrations and ChoK<sub>α</sub> expression but not with FAS or pACL. This study identified inhibition of ChoK<sub>α</sub> as a major cause of the observed change in PC levels following PI-103 treatment. We also showed the capacity of <sup>1</sup>H-MRS, a clinically well-established technique with higher sensitivity and wider applicability compared with <sup>31</sup>P-MRS, to assess response to PI-103. Our results show that monitoring the effects of PI3K inhibitors by MRS may provide a noninvasive PD biomarker for PI3K inhibition and potentially of tumor response during early-stage clinical trials with PI3K inhibitors. Cancer Res; 70(13); 5507–17. ©2010 AACR.</p></div>" @default.
- W4361244190 created "2023-03-31" @default.
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- W4361244190 date "2023-03-30" @default.
- W4361244190 modified "2023-10-14" @default.
- W4361244190 title "Data from The Phosphoinositide 3-Kinase Inhibitor PI-103 Downregulates Choline Kinase α Leading to Phosphocholine and Total Choline Decrease Detected by Magnetic Resonance Spectroscopy" @default.
- W4361244190 doi "https://doi.org/10.1158/0008-5472.c.6500205.v1" @default.
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