Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

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Dixon imaging techniques derive chemical shift-separated water and fat images, enabling the quantification of fat content and forming an alternative to fat suppression. Whole-body Dixon imaging is of interest in studies of obesity and the metabolic syndrome, and possibly in oncology. A three-point Dixon method is proposed where two solutions are found analytically in each voxel. The true solution is identified by a multiseed three-dimensional region-growing scheme with a dynamic path, allowing confident regions to be solved before unconfident regions, such as background noise. 2p-Phase unwrapping is not required. Whole-body datasets (256 3 184 3 252 voxels) were collected from 39 subjects (body mass index 19.8-45.4 kg/m 2 ), in a mean scan time of 5 min 15 sec. Water and fat images were reconstructed offline, using the proposed method and two reference methods. The resulting images were subjectively graded on a four-grade scale by two radiologists, blinded to the method used. The proposed method was found superior to the reference methods. It exclusively received the two highest grades, implying that only mild reconstruction failures were found. The computation time for a whole-body dataset was 1 min 51.5 sec 6 3.0 sec. It was concluded that wholebody water and fat imaging is feasible even for obese subjects, using the proposed method. Magn Reson Med 63:1659-1668, 2010. V C 2010 Wiley-Liss, Inc.Key words: three-point Dixon; whole-body MRI; water and fat separation; chemical shift imaging; fat suppression By utilizing the property of chemical shift, MR signals arising from different chemical species can be separated. Dixon techniques use a spectrum model to derive chemical shift-separated water and fat images from multiple source images acquired at different echo times (points). Dixon water-only images form an alternative to fat suppression techniques, such as short tau inversion recovery and spectral inversion recovery, that is potentially insensitive to magnetic field inhomogeneity.Due to the ability of fat quantification (1), Dixon imaging is of interest in studies of obesity and the metabolic syndrome. Whole-body Dixon imaging allows accurate investigation of adipose tissue distribution (2) and may also be useful in oncology (3).Dixon's original two-point method (4) assumed that the phase difference in the source images was caused by chemical shift only and did not account for other sources of phase distortion, such as amplitude of static field (B 0 ) inhomogeneity. However, the requirement of a homogeneous magnetic field can be relaxed by including B 0 inhomogeneity in the signal model. This has been done by acquiring an additional image, giving a three-point method (5-7), or by modification of the two-point method (8).Two main challenges for Dixon methods are the ambiguity of identifying water and fat, and 2p phase unwrapping of the B 0 field map. However, by acquiring the source images with constant echo spacing, these problems can be separated. In fact, phase unwrapping is not necessary for water and fat ...