Highlights of This Issue

Abstract

Paclitaxel, a chemotherapeutic agent that induces cell death via microtubule arrest, is the standard of care for metastatic triple-negative breast cancer, however response rates vary, and resistance often develops. Here, Oudin and colleagues report a novel mechanism of resistance to paclitaxel. Expression of pro-metastatic splice variants of the actin regulator Mena allows tumor cells to proliferate, invade and metastasize during Paclitaxel treatment by promoting microtubule dynamics and survival signaling. Paclitaxel treatment also elevates Mena protein levels in vitro and in vivo. These results may lead to improved biomarkers and therapeutic strategies for use of paclitaxel to treat metastatic disease.There is substantial preclinical evidence that drug-to-antibody ratio can have a significant impact on ADC physicochemical and pharmacological properties and has emerged as an important design parameter. Here, Burke and colleagues explored this with PEGylated glucuronide-MMAE linkers conjugated at 8-drugs per antibody, providing homogeneous ADCs that varied in hydrophobic nature. A series of drug-linkers with discrete PEG side chains containing up to 24 ethylene oxide units were evaluated and a threshold length of PEG8 was found to preserve ADC pharmacokinetic properties. Conjugates bearing PEG of sufficient length to preserve ADC exposure provided a wider therapeutic window relative to faster-clearing conjugates bearing smaller PEG side chains.Pretargeted radioimmunotherapy (PRIT) harnesses the tumor-targeting properties of mAbs and the rapid in vivo kinetics of small molecules, offering an attractive approach for moleculary targeted radiotherapy. Houghton and colleagues have adapted a strategy for pretargeted radioimmunotherapy based on the inverse electron demand Diels-Alder cycloaddition between a tetrazine (Tz) bearing radioligand and a trans-cyclooctene (TCO) modified mAb. In this issue, they report the first demonstration of the in vivo efficacy of such a system in a murine model of pancreatic ductal adenocarcinoma. Their PRIT system achieved a dose-dependent reduction in tumor volume and a promising dosimetry profile, suggesting that this approach could be suitable for clinical PRIT applications.The human epidermal growth factor receptor 2 gene (HER2), also known as ERBB2, is amplified and overexpressed in 16% of upper gastro-esophageal (UGI) adenocarcinomas. HER2 amplification levels and HER2 genomic heterogeneity were analyzed in UGI cancers from patients in the LOGiC (TRIO-013) clinical trial of chemotherapy with or without lapatinib, a small molecule inhibitor of EGFR and HER2 to assess a potential role in treatment responsiveness. Press and colleagues found that Asian participants and those less than 60 years of age had significant improvements in progression-free survival, particularly among those whose cancers had 5.01–10.0 and >10.0-fold amplification of HER2.