therapeutics molecular cancer highlights...to explore its role as a novel therapeutic target, avan...
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The Journal of Cancer Drug Discovery & Preclinical Development www.aacrjournals.org1619
A Glut1 Inhibitor ReducesCancer Growth In Vitro andIn Vivo
Liu et al. ______________Page 1672
Glucose transporter 1 (Glut1) isupregulated in almost all cancer cells.By coupling chemical synthesis withglucose uptake and cell proliferationassays, Chen and his colleaguesidentified a Glut1 inhibitor, WZB117.WZB117 was shown to inhibitglycolysis and ATP synthesis, to blockGlut1-mediated glucose transport,and to induce cell cycle arrest andsenescence. Daily intraperitonealinjection of WZB117 led to significantreduction in the size of tumors graftedon nude mice. WZB117 and drugscisplatin and paclitaxel showsignificant synergistic anticancereffects. All these indicate that Glut1 isa potential anticancer target andWZB117 is a candidate for developinganti-Glut1 anticancer drugs.
DZNeP/GemcitabineCombination in Pancreatic Cancer
Avan et al. _____________Page 1735
Enhancer of Zeste Homolog 2 (EZH2)is upregulated in pancreatic cancerand has been associated withgemcitabine chemoresistance and poorprognosis. To explore its role as anovel therapeutic target, Avan andcolleagues evaluated the interaction ofthe EZH2-inhibitor DZNeP withgemcitabine in pancreatic cancer cells,including primary cultures andspheroids growing in cancer stem cellsselective medium. This study showsthat DZNeP modulatesEZH2/H3K27me3 expression andinteracts synergistically withgemcitabine through reduction ofCD133+ cells, enhancement ofnucleoside transportershENT1/hCNT1 expression, andinhibition of cell migration. Theseresults provide a scientific rationale forfuture studies on this novel approachfor treatment of pancreatic cancer.
BKM120 Alters Microtubule Dynamics atHigh Concentrations
Brachmann et al. _______Page 1747
The pan-phosphoinositide 3-kinase(PI3K) inhibitor BKM120 was found,at high concentrations, to cause celldeath in various cellular systems,irrespective of their level of PI3Kaddiction. Transcriptional andbiochemical profiling studies wereused to identify the origin of theseunexpected and apparently PI3K-independent effects. Brachmannand colleagues show that BKM120, athigh concentrations, can act as amicrotubule destabilizer via directtubulin binding. Further analysis ofclinical data, such as the assessmentof mitotic markers in tumor biopsiesfrom patients treated with BKM120,will be required to fully confirm thatthe compound off-target activity isnot clinically relevant.
MolecularCancer
Therapeutics HighlightsAugust 2012 • Volume 11 • Number 8 Selected Articles from This Issue
MEDI0639 Targets Dll4
Jenkins et al. _______________________________________________Page 1650
Agents that target the Delta-like ligand 4 (Dll4)-Notch interaction have emerged as anew generation of molecules targeting tumor vasculature. Disrupting this interactionstimulates overdevelopment of the tumor vasculature, decreasing the effective bloodsupply to the tumor cells and restricting tumor growth. The work by Jenkins andcolleagues describes an investigational human therapeutic antibody, MEDI0639, whichbinds a functional epitope on Dll4 that has not been described previously. Targetingthis epitope results in potent modulation of endothelial cell function in vitro andmodifies human vessels in vivo, establishing MEDI0639 as a new potential therapeuticto target Dll4.
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2012;11:1619. Mol Cancer Ther Highlights of This Issue
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