Al-Saffar, N. M. S., Jackson, L. E., Raynaud, F. I., Clarke, P. A., Ramirez de Molina, A., Lacal, J. C., Workman, P., Leach, M. O. (2010) The Phosphoinositide 3-Kinase Inhibitor PI-103 Downregulates Choline Kinase a Leading to Phosphocholine and Total Choline Decrease Detected by Magnetic Resonance Spectroscopy. CANCER RESEARCH, 70 (13). pp. 5507-5517. ISSN 0008-5472

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Abstract

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 PIK3CA mutant HCT116 colon carcinoma cells with PI-103 resulted in a concentration-and time-dependent decrease in phosphocholine (PC) and total choline (tCho) levels (P < 0.05) detected by phosphorus (P-31)- and proton (H-1)-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 alpha (ChoK(alpha)), fatty acid synthase (FAS), and phosphorylated ATP-citrate lyase (pACL). However, a strong correlation (r(2) = 0.9, P = 0.009) was found only between PC concentrations and ChoK(alpha) expression but not with FAS or pACL. This study identified inhibition of ChoK(alpha) as a major cause of the observed change in PC levels following PI-103 treatment. We also showed the capacity of H-1-MRS, a clinically well-established technique with higher sensitivity and wider applicability compared with P-31-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. (C) 2010 AACR.

Item Type:	Article
Authors (ICR Faculty only):	Workman, Paul and Leach, Martin and Raynaud, Florence and Clarke, Paul
All Authors:	Al-Saffar, N. M. S., Jackson, L. E., Raynaud, F. I., Clarke, P. A., Ramirez de Molina, A., Lacal, J. C., Workman, P., Leach, M. O.
Uncontrolled Keywords:	PI3-KINASE P110-ALPHA INHIBITORS; MAS NMR-SPECTROSCOPY; BIOLOGICAL EVALUATION; PHOSPHOLIPID-METABOLISM; PHARMACODYNAMIC MARKERS; BREAST-CANCER; CARCINOMA CELLS; SREBP ACTIVITY; IN-VIVO; ACTIVATION
Funding Acknowledgement:	Association for International Cancer Research [03-304]; Cancer Research UK ; Engineering and Physical Sciences Research Council Cancer Imaging Centre in association with the Medical Research Council and Department of Health (United Kingdom) [C1060/A10334, C1060/6916]; Cancer Research UK [C309/A2187, C309/A8274]; Comunidad de Madrid [S-BIO/0280/2006]; EU [LSHG-CT-2006-037278]; Ministerio de Sanidad [RD06/0020/0016]; MICIN [SAF2008-03750]; National Health Service
Funding Text:	Association for International Cancer Research grant 03-304 (N.M.S. Al-Saffar), Cancer Research UK and Engineering and Physical Sciences Research Council Cancer Imaging Centre in association with the Medical Research Council and Department of Health (United Kingdom) grant C1060/A10334 and C1060/6916 (M.O. Leach and L. E. Jackson), Cancer Research UK grant C309/A2187 and C309/A8274 (P. Workman, F. I. Raynaud, and P. A. Clarke), and Comunidad de Madrid (S-BIO/0280/2006), EU grant (LSHG-CT-2006-037278), Ministerio de Sanidad (RD06/0020/0016), and MICIN (SAF2008-03750; J.C. Lacal). P. Workman is a Cancer Research UK Life Fellow. The Institute of Cancer Research coauthors acknowledge National Health Service funding to the Biomedical Research Centre.
Research teams:	ICR divisions > Cancer Therapeutics > Signal Transduction & Molecular Pharmacology ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) ICR divisions > Radiotherapy and Imaging > Magnetic Resonance
Depositing User:	Users 10 not found.
Date Deposited:	20 Jul 2010 08:31
Last Modified:	16 Aug 2012 11:23
URI:	http://publications.icr.ac.uk/id/eprint/9752

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