Highlights of This Issue

Abstract

LHRH receptors are expressed on the cell membrane of prostate cancer cells and may provide novel therapeutic targets in patients with treatment refractory prostate cancer. Liu and colleagues report a phase I trial of AEZS-108, a hybrid molecule that couples an LHRH agonist with doxorubicin. The agent was well tolerated in heavily pretreated patients and showed early signs of efficacy. In addition, the autofluorescent properties of doxorubicin permitted visualization of internalization in circulating tumor cells, highlighting a potential pharmacodynamic predictive marker for future use of this drug.Demcizumab, a humanized antibody targets the Notch pathway component delta-like ligand 4 (DLL4). Notch plays a critical role in the maintenance of tumor cells with stem-cell properties. Smith and colleagues conducted this phase I trial of demcizumab in patients with advanced solid tumors. Downregulation of stem cell-related genes and upregulation of vascular/endothelial genes occurred starting at 2.5 mg/kg every other week. Patients treated at 10 mg/kg every other week had disease stabilization and decreases in tumor size and prolonged exposure resulting in the emergence of delayed cardiac toxicity. Demcizumab shows promising anticancer activity and novel toxicities warranting further investigation.Resistance to the EGFR inhibitors cetuximab or panitumumab in colorectal cancer is caused by the emergence of mutations in the RAS pathway. In biopsies from relapsed patients, however, only a fraction of cells carry RAS mutations, suggesting that wild-type cells can also survive the treatment. Hobor and colleagues report that sensitive cells grow in the presence of cetuximab when in the company of their resistant derivatives. They find that cells bearing acquired RAS mutations over-secrete the EGFR ligands TGFα and amphiregulin, which protect the surrounding wild-type cells. This paracrine network can be targeted to increase the efficacy of anti-EGFR therapies.Genotype-directed therapy using kinase inhibitors is the standard of care for subsets of lung cancer patients whose tumors harbor oncogenic alterations. These alterations are more frequently detected in never smokers with non-small cell lung cancer, but not all patients harbor a known oncogenic alteration. To identify additional targetable alterations, Capelletti and colleagues screened 576 adenocarcinomas from never smokers. They identified FGFR3-TACC3 rearrangements in three patients of this cohort. In vitro experiments demonstrated that this alteration is oncogenic and sensitive to pan-FGFR inhibitors. These findings suggest that patients harboring FGFR3-TACC3 rearrangement should be considered for clinical trials featuring FGFR inhibitors.