Highlights of This Issue

Abstract

The ATR kinase generates signals in response to the DNA replication intermediates and DNA strand breaks commonly caused by many types of anticancer therapeutics. To study the respective contributions of ATR pathway components to cell growth and survival, Wilsker and colleagues analyzed the drug responses of human cancer cells with targeted mutations in CDK2, ATR, or CHK1. Enhancement of sensitivity to distinct classes of drugs was highly target specific. These studies show how an isogenetic cell system can be used to comparatively evaluate prospective therapeutic targets.Aberrantly activated Hedgehog signaling pathway has been linked to multiple cancers and therefore represents a promising therapeutic target. Rohner and colleagues show that PF-5274857 is a highly potent and selective antagonist of Smoothened with excellent pharmacokinetic and pharmaceutical properties. PF-5274857 shows a robust antitumor activity in a mouse model of medulloblastoma, and the downregulation of pharmacodynamic marker Gli1 is closely linked to the tumor growth inhibition. In addition, PF-5274857 is found to effectively penetrate the blood brain barrier. Thus, PF-5274857 is an attractive clinical candidate to treat tumors including brain tumors and brain metastasis.A key regulator of cell cycle and proliferation, c-myc is commonly overexpressed in leukemia. The c-myc promoter contains a guaninerich sequence (PU27) capable of forming quadruplex (four-stranded) DNA, which may negatively regulate c-myc transcription. To explore its significance on the regulation of c-myc and leukemic growth, leukemia cells were treated with an oligonucleotide encoding the genomic PU27 sequence. PU27 induced cell cycle arrest and cell death associated with suppression of c-myc mRNA/protein expression. It was abundantly taken into cells, inherently stable, had no effect on normal cells, and overall shows therapeutic promise for the treatment of multiple forms of leukemiaAndrogen receptor (AR) gain-of-function is a common mechanism of resistance to various hormonal therapies in advanced prostate cancer and previous studies have suggested that suppression of superoxide dismutase-2 (SOD2) expression may contribute to AR function in resistant tumors. Thomas and Sharifi show that replacing SOD activity with small molecule SOD mimetics suppresses AR function, in vitro and in vivo prostate cancer survival and growth. These findings suggest a new therapeutic modality for the treatment of advanced prostate cancer that stands apart from more traditional AR antagonists and androgen synthesis inhibitors and may be translated to the clinic.