Highlights of This Issue

Abstract

Folate receptor-α (FRα) is highly expressed on several tumor types that urgently call for new therapies, including many ovarian, endometrial, and non-small cell lung cancers. Here, Ab and colleagues report on the development of IMGN853 (mirvetuximab soravtansine), the first FRα-targeting antibody–drug conjugate (ADC). The design of the ADC, including selection of its antibody, linker, and maytansinoid cytotoxic agent, was determined by a series of experiments that provide insight into ADC optimization and support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors.Multidrug resistance (MDR) in tumors is a significant obstacle to the success of chemotherapy in several cancers. RNA interference–based destruction of complementary mRNA molecules has emerged as a powerful strategy for cancer. However, due to lack of safer delivery strategies, their use has been limited. In this study, Talekar and colleagues developed the siRNA-encapsulated hyaluronic acid–based self-assembling nanoparticles targeting drug resistance pumps and the glycolytic pathway and showed increased tumor accumulation and efficacy in both the wild-type and paclitaxel resistance model. The data indicated that concurrent silencing of MDR-1 and PKM-2 genes improves the efficacy of paclitaxel against MDR ovarian cancer.CDK5 inhibition abates activation of the centrally important KRAS effector RAL in pancreatic ductal adenocarcinoma cells, suggesting a clinically feasible therapeutic strategy for inhibiting KRAS function in pancreatic cancer. Hu and colleagues evaluated the efficacy of combined inhibition of two of the main KRAS effector pathways, RAL and PI3K-AKT, in a series of patient-derived xenograft (PDX) models of pancreatic cancer. Strong and consistent responses to a combination of the multi-CDK inhibitor dinaciclib and the AKT inhibitor MK-2206 were seen, including several complete responses. Based on these results, a multicenter Phase I clinical trial of this combination has been initiated.Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific antigen that was previously identified in glioblastoma multiforme patients. Hamblett and colleagues generated AMG 595, an anti-EGFRvIII-specific antibody conjugated to DM1 via a noncleavable linker. Following internalization into EGFRvIII-expressing cells, AMG 595 was shown to be potent in vitro. Efficacy of AMG 595 in vivo was observed in multiple subcutaneous xenograft models and an orthotopic xenograft model. The data provide the basis to evaluate AMG 595 in patients with EGFRvIII-expressing glioblastoma multiforme.