Highlights of This Issue

Abstract

The receptor tyrosine kinase Met and its ligand hepatocyte growth factor/scatter factor are major metastasis targets. In this study, Winter and colleagues developed small molecule antagonists for the interaction between those two proteins using a fragment-based approach. The authors were able to identify small lead compounds that inhibit cell migration and prevent tumor formation in cell-based assays. Developing inhibitors against protein–protein interactions using fragment-based approaches could be the key to unlocking previously thought “undruggable” protein–protein interactions to drug development campaigns, especially when no structural information of the target interface is available.Chemoresistance presents a major limitation to the efficacy of cancer treatment. The current study describes an original approach for sensitizing colorectal liver metastasis to conventional chemotherapy, using a signal-interfering DNA called DT01. DT01 inhibits DNA repair by inducing “false” DNA damage signals. DT01 has recently undergone a phase I clinical trial on melanoma skin metastases with promising results in association with radiotherapy. Here, Herath and colleagues investigated the therapeutic efficacy of associating DT01 with oxaliplatin and 5-fluorouracil in preclinical models. This work highlights that combining DT01 with chemotherapy may be a safe and effective therapeutic strategy in the treatment of colorectal liver metastases.ML264 is a third-generation small molecule compound developed with the goal of inhibiting the growth of colorectal cancer cells by targeting oncogenic Krüppel-like factor 5 (KLF5). Ruiz de Sabando and colleagues demonstrated that ML264 has multiple effects on colorectal cancer cell lines, such as cessation of mitotic figures through modification of the cell-cycle profile. ML264 can also inhibit the growth of colorectal tumors in an established xenograft mouse model, achieved by the reduction in proliferation and inhibition of KLF5 and EGR1, a transcriptional activator of KLF5. These findings suggest that ML264 may be a potential novel therapeutic agent for colorectal cancer.Conventional photodynamic therapy (PDT) using photosensitive dyes has unsolved problems due to systemic photosensitive adverse effect and lack of sufficient, as well as continuous, accumulation of photosensitizers in tumor tissues. Takehara and colleagues developed a conditionally replicating adenovirus-mediated delivery system for photosensitive cytotoxic fluorescent protein KillerRed as a novel PDT. This treatment demonstrated the antitumor effect not only for subcutaneous xenograft tumor but also for intraperitoneal lymph node metastasis of human cancer in mouse models. This adenovirus-mediated delivery system of KillerRed is a novel strategy to improve the anticancer potential of PDT.