Highlights of This Issue

Abstract

The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in over 95% of well-differentiated/dedifferentiated liposarcomas (WD/DDLPS). Here, Zhang and colleagues explored the effects of NVP-LEE011, a novel selective inhibitor of CDK4/6, on a panel of human liposarcoma cell lines in vitro and patient-derived tumor xenografts in vivo. NVP-LEE011 induced retinoblastoma protein-dependent cell-cycle arrest, and decreased cell proliferation as well as tumor glucose metabolism, which resulted in tumor growth inhibition or regression. These findings validate the critical role of CDK4 in the growth of liposarcoma and suggest the potential application of its inhibitor, NVP-LEE011, in liposarcoma treatment.MLN8237 (alisertib) is a selective Aurora A inhibitor that displays additive and synergistic antitumor activity in combination with taxanes in preclinical models of breast cancer. An exposure–efficacy model was generated with the preclinical combination of MLN8237 and paclitaxel. Exposures of both agents achieved in patients were mapped onto the model to predict which combination of exposures would lead to the greatest antitumor activity based on clinically feasible doses. This model was used as a factor in selecting the phase 2 dose for these agents in cancer patients. Similar approaches can guide dose-schedule optimization for combinations of other therapeutic agents.The effect of erlotinib remains modest in non–small cell lung cancer (NSCLC) patients with wild-type (wt) epidermal growth factor receptor (EGFR). To improve the efficacy of erlotinib, Dermawan and colleagues tested the combination of erlotinib with quinacrine, which inhibits the FACT (facilitates chromatin transcription) complex required for NF-κB activity. This drug combination showed highly synergistic effect in three representative NSCLC cell lines resistant to anti-EGFR therapy. Moreover, genes that were strongly suppressed by the combination in NSCLC cells predicted the poor survival in lung adenocarcinoma patients. This experimental evidence provides the basis for testing this novel combination in clinical trial.