Highlights of This Issue

Abstract

Targeted CHK1 inhibition is an attractive approach with the potential for rational combination with multiple chemotherapies. The critical issue is the therapeutic index in combination, necessitating careful selection of compounds for progression. Guzi and colleagues identified SCH 900776 using a pathway-oriented functional approach and targeted medicinal chemistry. Mechanism-based biomarkers were used to quantitatively assay checkpoint override phenotypes. This strategy exposed the risk of functional antagonism, highlighting a need for sufficient CHK1 selectivity. The biomarkers were translated to preclinical animal species, allowing in vivo assessment of SCH 900776 mechanism engagement and tolerability. In xenograft models, doses of SCH 900776 associated with robust biomarker activation, and improved tumor response was not associated with enhanced toxicity of gemcitabine on hematological parameters in BALB/c mice. Administration of SCH 900776 presents a clinical opportunity to selectively enhance cell death responses in tumor cell backgrounds.Since its discovery, endostatin, an important regulator of angiogenesis, has failed to have significant clinical impact. In this issue, Shin and colleagues enhance endostatin performance by tethering a mutant human endostatin to an anti-HER2 antibody. The antibody-endostatin fusion protein has a longer half life than endostatin, localizes to the tumor, and shows superior antiangiogenic efficacy in vitro and antitumor activity in vivo in tumor xenograft models. This promising approach points the way to more effective endostatin use in the clinic for breast cancer and other solid tumors and represents a new class of antiangiogenic agents.Understanding mechanisms on leukemia differentiation may provide help for designing safe and specific differentiation therapy to treat leukemia. Yang and colleagues report that the induction of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) and IL-24 delE5, a mda-7/IL-24 splice variant, contributes to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced monocytic differentiation, and they also show the specific differentiation induction roles of mda-7/IL-24 and IL-24 delE5 in acute myeloid leukemia (AML) cells. These studies characterize mda-7/IL-24 and IL-24 delE5 as novel genes associated with leukemic cell differentiation and bring new insights into the regulation of AML cell differentiation.Genetic screens identifying molecules whose inactivation kills cancer cells carrying a specific genetic alteration (synthetic lethality) are widely used to select new therapeutic targets. Hattori and colleagues show an important limitation of synthetic lethal screens. They identify the checkpoint kinase CHK1 as a therapeutic target in cancers lacking the tumor suppressor BRCA2. However, CHK1 inhibition is rendered ineffective by additional mutations like activated KRAS or mutant TP53 typical of pancreatic cancers arising in BRCA2 mutation carriers. Gemcitabine overcomes this resistance. Synthetic lethal screens that fail to consider the full genetic context of specific malignancies may not identify valid therapeutic targets.