April 1 Clinical Cancer Research Highlights

The relatively large molecular size of therapeutic monoclonal antibodies raises concerns regarding their ability to effectively distribute throughout tumor tissues. Using immunohistochemistry, Baker and colleagues mapped the location of trastuzumab at micromolar resolution in the context of a tumor microenvironment. Considerable heterogeneity was observed, with neighboring, perfused vessels often exhibiting different patterns of trastuzumab distribution. Overall, trastuzumab penetration was found to be incomplete and could not be explained by vascular density, perfusion, or HER2 expression status. This work highlights the importance of elucidating factors that influence antibody distribution in tumor tissues and suggests that limited penetration is a mechanism for resistance to therapy.  

 

The ability to target tumor cells with systemic gene therapy has important therapeutic applications. Here, Pirollo and colleagues show that a nanosized, liposome-based gene medicine delivery system is effective at targeting bladder cancer. When administered intravenously, the complex efficiently delivered plasmid DNA encoding RB94 (a truncated protein that has potent tumor suppressor activity) to both subcutaneous and orthotopic tumors in animal models of bladder cancer. In mice bearing subcutaneous human bladder tumors, the combination of the nanocomplexed RB94 along with the chemotherapeutic agent gemcitabine resulted in significant tumor growth inhibition and the induction of apoptosis. These preclinical data suggest that this gene delivery system may be effective in treating genitourinary cancer in the clinical setting. 

The retinoblastoma tumor-suppressor protein (pRB) is absent in many human cancers. In this study, Derenzini and colleagues investigated whether the absence of pRB has an effect on the response to adjuvant therapy in patients with breast cancer. The absence of pRB expression was found to be strongly associated with a good clinical outcome in patients treated with standard systemic chemotherapy, but not with endocrine therapy alone. Additionally, using in vitro cellular assays, Derenzini and colleagues found that treatment with chemotherapeutic agents significantly reduced the growth rate of RB1-silenced cells, but not of control cells. These data suggest that treating patients who have pRB-negative breast cancer with adjuvant chemotherapy may improve their clinical outcome. 

A Mouse Model for Studying Met Inhibitors