Highlights of This Issue Free

A linker-drug platform was built based on a cleavable linker-duocarmycin payload for the development of new generation antibody–drug conjugates (ADC). Upon cleavage, the designated linker-drug, vc-seco-DUBA, liberates a DNA-alkylating cytotoxic drug that induces cell death in both dividing and nondividing cells. In this study, Dokter and colleagues profiled a vc-seco-DUBA–based HER2-targeting ADC (SYD983/SYD985) in preclinical studies for efficacy and safety. They show a favorite profile for SYD983/SYD985 that warrants further clinical development. This new generation linker-drug shows promise as a platform to create effective and safe ADCs with a diversity of mAbs for numerous indications in oncology.

A novel mixed lineage leukemia 5 isoform, MLL5β, has been reported to be essential for the activation of E6 and E7 gene in HPV16/18-positive cervical cancer cells. In the present study, Nin, Yew, and colleagues discovered that targeted silencing of MLL5β using RNA interference selectively induced the cytotoxicity of HPV16/18-positive tumor cells in vitro and in vivo while sparing HPV16/18-negative cells. Furthermore, MLL5β-siRNA was shown to evoke cisplatin-like gamma-irradiation sensitization with better specificity in HPV16/18 tumor cells. The study highlights the potential application of MLL5β-siRNA as a novel therapeutic agent for HPV16/18-induced cervical cancers.

Mesothelin has been clinically validated as an immunotoxin target for mesothelioma, ovarian cancer, and pancreatic cancers, but there is a need for more efficacious, less immunogenic therapies. Here, Scales and colleagues describe the generation of a novel antimesothelin antibody conjugated to auristatin E (MMAE), a potent microtubule-disrupting agent. αMSLN-MMAE specifically inhibited proliferation of mesothelin-expressing cells in vitro and, more importantly, in vivo in six xenograft models of ovarian, pancreatic, and mesothelioma expressing clinically meaningful levels of mesothelin. αMSLN-MMAE could therefore be potentially efficacious against such cancers and phase I clinical trials are ongoing.

Kinase inhibitors are often pleiotropic. Here, Gridling and colleagues report the protein interaction networks for two multikinase inhibitors, dasatinib and sunitinib, in lung cancer patient tissues using chemical and phosphoproteomics. Comparison with cell lines and mouse xenografts showed that several targets identified were only present in tumor tissues. In xenografts, these were mostly of mouse origin suggesting they originated from the tumor microenvironment. Furthermore, several activated signaling pathways were targeted both in cancer cells and the microenvironment. Thus, this approach can generate a systems view of proteins and signaling pathways that are simultaneously engaged by multitargeted drugs in cancer cells and the tumor microenvironment.