Highlights of This Issue

Abstract

In cancer treatment, drug combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. O'Neil, Benita, Feldman, and colleagues performed a high-throughput oncology drug combination screen of 583 doublet combinations and found that synergy is relatively rare. However, both well-known and novel synergistic drug combinations were identified. One novel combination, a Wee1 inhibitor and an mTOR inhibitor, potently and synergistically inhibits cancer cell growth both in vitro and in vivo and is well tolerated in vivo. This approach identified novel combinations with improved efficacy that would be difficult to reliably predict based on our current understanding of cancer cell biology.Durable responses of BRAFV600E inhibitor vemurafenib have been hampered by drug resistance in human melanoma. Here, Feng and colleagues created compound DETD-35, a derivative of plant sesquiterpene lactone deoxyelephantopin, which significantly inhibits intrinsic and acquired vemurafenib resistance tumor growth in xenograft mice through suppression of MEK/ERK signaling reactivation and promoting ROS-induced apoptosis in melanoma cells. The antitumor effect of DETD-35 combined with vemurafenib is superior to vemurafenib or DETD-35 treatment alone. These data suggest the therapeutic potential of DETD-35 in BRAFV600E mutant or acquired vemurafenib resistance melanoma as a single or adjuvant agent.Antibody–drug conjugates (ADC) offer increased therapeutic efficacy with reduced side effects compared with chemotherapy. Currier, Ackerman and colleagues explore the role of alternative tumor targeting agents formed through fusion of a disulfide-rich engineered integrin-binding peptide, known as a knottin, to an antibody Fc domain. Knottin–Fc–drug conjugates (KFDC), attached to monomethyl-auristatin-F through a PEG linker, were synthesized via a non-natural amino acid incorporated during cell-free protein synthesis. The KFDC significantly prolonged tumor regression and survival in a xenograft model compared with a nontargeted conjugate or drug alone, thus providing a basis for further development of KFDCs for targeted drug delivery applications.In the present study, Morrison and colleagues discovered for the first time that the transmembrane protein SLITRK6 is overexpressed in bladder cancer. Moreover, the authors investigated SLITRK6 as a target for antibody–drug conjugate (ADC) treatment of advanced urothelial cancer. AGS15E, a SLITRK6-specific ADC conjugated with Monomethyl Auristatin E turned out to be the most potent among all ADCs generated. When compared with its Momomethyl Auristatin F counterpart, AGS15E showed superior antitumor activity in SLITRK6-highly expressed cancer xenografts as well as others with a broad range of SLITRK6 expression. AGS15E is currently in Phase I clinical trials for advanced urothelial cancer.