Highlights of This Issue

Clinical benefit observed with drugs targeting oncogenic kinases is often transient due to the appearance of acquired resistance. Moreover, fully effective exposures of many such drugs cannot be achieved for tumors or metastases located within the brain, due to the blood–brain barrier. Fogliatto and colleagues present original data on NMS-E973, a novel second-generation inhibitor of Hsp90 with antitumor efficacy against a broad range of preclinical tumor models. Notably, in addition to models of acquired drug resistance, NMS-E973 is also active against intracranially implanted tumor xenografts, highlighting the therapeutic potential of this new class of molecules.

Although the ETS2 gene is involved in an array of intracellular pathways through its canonical transcription factor function, its role in non–small cell lung cancer (NSCLC) pathogenesis remains elusive. Kabbout and colleagues studied the expression and global function of ETS2 in human NSCLC tissues and multiple lung cancer cell lines. Decreased ETS2 expression was prevalent in lung tumors, predicted shorter time to patient recurrence, and heightened lung cancer cell proliferation, migration, and invasion through activation of HGF signaling and MET oncogene function. Decreased ETS2 expression and function may represent a novel mechanism for uncontrolled HGF/MET signaling and activity in NSCLC.

The CCL2/CCR2 axis is essential in the recruitment of inflammatory monocytes (CCR2⁺) from the bone marrow to the tumor and premetastatic site where these cells become macrophages. Sanford and colleagues demonstrate that monocyte mobilization from the bone marrow to the blood predicts survival in patients with pancreatic cancer. Human pancreatic tumors highly expressed CCL2 and were infiltrated by abundant immunosuppressive CCR2⁺ macrophages. A novel CCR2 antagonist prevented inflammatory monocyte recruitment to tumors and premetastatic livers in murine pancreatic cancer, which decreased tumor growth and metastasis. These results have set the foundation for a clinical trial using CCR2 blockade in patients with pancreatic cancer.

Interleukin-6 is involved in the pathogenesis of B-cell malignancies and is responsible for systemic manifestations in Castleman disease, a rare, atypical lymphoproliferative disorder. Siltuximab is a chimeric, high-affinity monoclonal antibody that neutralizes human interleukin-6. Kurzrock and colleagues conducted a phase I study in patients with Castleman disease, B-cell non-Hodgkin lymphoma, or multiple myeloma, demonstrating that siltuximab is well tolerated across multiple dose levels and upon prolonged treatment. A high rate of clinical and radiologic response was seen in patients with Castleman disease. A dose of 12 mg/kg every 3 weeks was recommended based on the high response rates in Castleman disease and sustained C-reactive protein suppression.