Tumor Targeting with Integrin αvβ3 and MMP-2
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.
Hec-1 Inhibitor against Breast Cancer
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.
Discovery of a Covalent EGFR Mutant Selective Inhibitor
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, a Novel Antibody–Drug Conjugate Targeting Mesothelin
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.
- ©2014 American Association for Cancer Research.