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The Cancer Drug Development Journal: From Concept to Clinic www.aacrjournals.org1219

RITA Efficacy in Ewing’sSarcoma

Di Conza et al. _________Page 1247

Reactivation of p53 and Induction ofTumor cell Apoptosis (RITA) is apromising compound for treatment ofhuman cancer by reactivating theoncosuppressor p53. To explore RITAefficacy in Ewing’s sarcoma, one ofthe most frequent bone cancers inadolescence, Di Conza and colleaguesprovided evidence that RITA iseffective in reducing growth andtumorigenic potential of Ewing’ssarcoma cells independently of p53.Particularly, RITA causesdownregulation of IGF-1R, animportant oncogenic mark of thistumor. This work suggests thepossibility of RITA adopting anadditional mechanism of action,expanding its field of application,and envisages the promising use ofRITA derivative as a potentialtreatment for Ewing’s sarcomas.

Characterization of a NewClass of GlutaminaseInhibitors

Katt et al.______________Page 1269

There has been a renaissance in ourunderstanding of the Warburg effectand the importance of the metabolicchanges that accompany and helpsustain cancer progression. Here, Kattand colleagues provide an expandedstructure-activity relationship for 968,a novel inhibitor of glutaminase C thatis a key enzyme responsible forsatisfying the glutamine addiction ofcancer cells. These studies now offer anew strategy for achieving theallosteric inhibition of this importantmetabolic enzyme and hopefully willhelp to inform future efforts towarddeveloping more potent inhibitors andeventually improved cancer therapies.

Affinity and Tumor Uptake

Orcutt et al.____________Page 1365

A bispecific antibody was engineered for use in pretargetedradioimmunotherapy, withradiometal chelate binding sites with affinity varying from KD = 10 pmol/L - 20 nmol/L, dependingon the radiometal (177Lu vs. 111In)and the particular chelator (DOTA vs.Benzyl DOTA). This enableddetermination of the effect of bindingaffinity on accumulation of the smallmolecule radiometal chelate in thetumor. KD < 400 pM providesmaximum label uptake, consistentwith a simple mathematical modelthat predicts the required affinity formaximal uptake as a function ofantigen expression level,transcapillary transport rate, andendocytosis rate.

A New Structural Class for Inhibitionof the AR in Prostate Cancer

Helsen et al._______________________Page 1257

Despite the initial effectiveness of current anti-androgens in disseminated prostate cancer,therapy resistance typically emerges after 18months. The androgen receptor (AR), however,remains a therapeutics target because its activityis restored. Here, we describe the detection andcharacterization of a novel class of ARantagonists that inhibit the expression ofandrogen-regulated genes and reduce theproliferation of AR-positive prostate cancer celllines. MEL-3 not only has an improved in vitrotherapeutic profile compared to bicalutamide,but it also remains active on models of resistanceto bicalutamide and hydroxyflutamide, whichindicates that it might ensure follow-uptreatment in these forms of therapy resistance.

MolecularCancer

Therapeutics HighlightsJune 2012 • Volume 11 • Number 6 Selected Articles from This Issue

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