Highlights of This Issue

Abstract

Better detection and treatment of cancer needs improved targeting and delivery of imaging and therapeutic agents to tumors. In this report by Crisp and colleagues, MMP-2/9-activatable cell-penetrating peptides have been conjugated with an αvβ3-binding domain, cyclic-RGD. In vivo, such dual targeting produced highly increased tumor fluorescence compared with an untargeted peptide, and enhanced depth penetration. Dually targeting the chemotherapeutic monomethylauristatin E improved the drug's efficacy in mammary MDA-MB-231 orthotopic human and syngeneic Py230 murine models with significant tumor regression and survival. This novel strategy could be useful in optical tumor imaging and chemotherapeutic delivery.NDC80/Hec1 is part of the kinetochore complex and is overexpressed in human cancers. In this study, Huang and colleagues explore the potential of the novel pharmacokinetically improved Hec1-targeted compound TAI-95 in breast cancer. Nine out of eleven breast cancer cell lines tested, including multidrug-resistant cell lines, were shown to be sensitive to nanomolar concentrations of TAI-95 in vitro. Moreover, oral administration of TAI-95 significantly inhibited breast tumor growth in vivo. TAI-95 was also shown to downregulate P-glycoprotein and increase the potency of cytotoxic P-glycoprotein substrates. This study highlights the potential of TAI-95 as a novel drug in breast cancer treatment.There is a clinical need to identify next generation EGFR tyrosine kinase inhibitors (TKI) that can overcome clinically arising drug-resistant EGFRT790M mutations while sparing wild-type EGFR (EGFRWT) to avoid on-target toxicity. Here, Tjin Tham Sjin and colleagues describe the in vitro and in vivo characterization of EGFR mutant-selective irreversible diaminopyrimidine inhibitors that have low affinity for EGFRWT. The lead compound potently inhibits EGFRT790M, both in vitro and in vivo, but more importantly spares EGFRWT. Such a compound offers superiority over first and second generation EGFR TKIs and is showing promising clinical activity with a 67% RECIST partial response rate with no dose-related signs of EGFRWT-associated toxicities.Anetumab ravtansine is an antibody–drug conjugate (ADC) consisting of anti-mesothelin antibody conjugated to DM4, a potent microtubule inhibitor. Here, Golfier, Kopitz and colleagues demonstrate its specific effect on proliferating mesothelin-positive cancer cells in vitro. Moreover, clinically relevant doses of anetumab ravtansine resulted in tumor eradication in several subcutaneous, orthotopic, and patient-derived xenograft models in vivo. Importantly, anetumab ravtansine demonstrated a killing bystander effect on neighboring mesothelin-negative tumor cells contributing to the antitumor activity of ADC. Anetumab ravtansine has potential to be efficacious in a wide variety of tumors and is currently in clinical evaluation.