Nagji et al., Page 2834

The ability to predict the efficacy of molecularly targeted therapies for non-small cell lung cancer (NSCLC) for an individual patient remains problematic. Nagji and colleagues used the refined coexpression extrapolation (COXEN) algorithm to identify tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat (histone deacetylase inhibitor) and Velcade (proteasome inhibitor). Importantly, they provide an in silico method to generate biomarkers that predict tumor sensitivity to novel molecularly targeted therapies. Use of this refined COXEN methodology has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost.

Xiao et al., Page 2714

Since αvβ3 integrin plays a key role in angiogenesis and metastasis of human tumors, ligands against this integrin are potentially useful in targeted therapy and cancer imaging. Xiao and colleagues report that a novel RGD peptide ligand, LXW7 with a built-in handle, was identified using OBOC combinatorial chemistry. LXW7 demonstrated high targeting efficacy and specificity for the αvβ3 integrin expressed in tumor cells. Moreover, LXW7 permits easier functionalization for payload conjugation without attenuating the binding affinity of the peptide compared with RGD cyclopentapeptide ligands. LXW7, therefore, has great potential as a highly efficient peptide ligand for targeted imaging and drug delivery.

Okamoto et al., Page 2785

Non-small cell lung cancer (NSCLC) with an activating mutation of the epidermal growth factor receptor (EGFR) ultimately develops resistance to EGFR tyrosine kinase inhibitors (TKI). Okamoto and colleagues show that EGFR mutation–positive NSCLC (HCC827) cells engineered to stably overexpress HGF (HCC827-HGF) exhibit gefitinib resistance. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib suppressed their growth in HCC827-HGF cells both in vitro and in vivo. Our findings suggest that the addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation.

Macarulla et al., Page 2844

Aurora A kinase (AAK), a protein kinase critical for tumor proliferation and survival, is a novel target for cancer treatment. MLN8054, an oral small-molecule AAK inhibitor, produces broad preclinical antitumor activity. In this Phase I study, Macarulla and colleagues evaluated safety, pharmacokinetics, and pharmacodynamics in serial tumor and skin biopsies. Total daily doses of 70 or 80 mg led to marked changes in mitotic cell chromosome alignment and spindle bipolarity in some patients. These results provide evidence for the dominant mechanism to inhibit AAK and support ongoing efforts to target this enzyme in the clinical treatment setting.