Helsen et al. Page 1257

Despite the initial effectiveness of current anti-androgens in disseminated prostate cancer, therapy resistance typically emerges after 18 months. The androgen receptor (AR), however, remains a therapeutics target because its activity is restored. Here, we describe the detection and characterization of a novel class of AR antagonists that inhibit the expression of androgen-regulated genes and reduce the proliferation of AR-positive prostate cancer cell lines. MEL-3 not only has an improved in vitro therapeutic profile compared to bicalutamide, but it also remains active on models of resistance to bicalutamide and hydroxyflutamide, which indicates that it might ensure follow-up treatment in these forms of therapy resistance.

Di Conza et al. Page 1247

Reactivation of p53 and Induction of Tumor cell Apoptosis (RITA) is a promising compound for treatment of human cancer by reactivating the oncosuppressor p53. To explore RITA efficacy in Ewing's sarcoma, one of the most frequent bone cancers in adolescence, Di Conza and colleagues provided evidence that RITA is effective in reducing growth and tumorigenic potential of Ewing's sarcoma cells independently of p53. Particularly, RITA causes downregulation of IGF-1R, an important oncogenic mark of this tumor. This work suggests the possibility of RITA adopting an additional mechanism of action, expanding its field of application, and envisages the promising use of RITA derivative as a potential treatment for Ewing's sarcomas.

Katt et al. Page 1269

There has been a renaissance in our understanding of the Warburg effect and the importance of the metabolic changes that accompany and help sustain cancer progression. Here, Katt and colleagues provide an expanded structure-activity relationship for 968, a novel inhibitor of glutaminase C that is a key enzyme responsible for satisfying the glutamine addiction of cancer cells. These studies now offer a new strategy for achieving the allosteric inhibition of this important metabolic enzyme and hopefully will help to inform future efforts toward developing more potent inhibitors and eventually improved cancer therapies.

Orcutt et al. Page 1365

A bispecific antibody was engineered for use in pretargeted radioimmunotherapy, with radiometal chelate binding sites with affinity varying from KD = 10 pmol/L - 20 nmol/L, depending on the radiometal (177Lu vs. 111In) and the particular chelator (DOTA vs. Benzyl DOTA). This enabled determination of the effect of binding affinity on accumulation of the small molecule radiometal chelate in the tumor. KD < 400 pM provides maximum label uptake, consistent with a simple mathematical model that predicts the required affinity for maximal uptake as a function of antigen expression level, transcapillary transport rate, and endocytosis rate.