New Target Devised for Antiangiogenic, Antitumoral Therapies

Spanish researchers have demonstrated that the antibody-based blocking of ephrinB2, a protein involved in angiogenesis and lymphoangiogenesis, may represent an effective strategy for the development of antiangiogenic and antitumoral therapies.

The study’s findings appeared in the May 2012 issue of Blood, the journal of the American Society of Hematology. Spanish National Cancer Research Center (CNIO; Madrid, Spain) researchers led by Jorge L. Martínez-Torrecuadrada, from the proteomics unit, created highly specific human antibodies against ephrin-B2 employing a phage display-line approach. These specific antibodies were able to suppress endothelial cell migration and tube formation in in vitro assays. Moreover, systemic treatment of mice xenografted with lung, pancreatic, or colon carcinoma cells resulted in a considerable decrease in the amount of blood and lymphatic vessels.

Along with this, an extreme suppression of the tumor growth was observed in every xenograft mouse model used. Therefore, these results validated ephrinB2 as a potential therapeutic target in tumor angiogenesis and lymphangiogenesis and demonstrated that the ephrinB2-specific antibodies developed in this study may be suitable as leads for the development of new improved antiangiogenic therapies, which can be used alone or can complement or synergize with other existing antiangiogenic cancer therapies or other angiogenesis-related pathologies.

Angiogenesis is a complicated process by which new blood vascular vessels grow from preexisting ones. In adulthood and under physiologic conditions, this process only occurs in specific instance, such as wound healing or in the menstrual cycle, but it is also an important factor in several pathologies such as cancer, in which the tumor triggers the formation of new blood vessels. This new vasculature provides the tumor with oxygen and nutrients, allowing these cells to grow, invade neighboring tissue and eventually spread to distant organs.

In addition to blood vasculature, tumor growth induces the development of lymphatic vessels in a similar process called lymphangiogenesis that plays a key role in tissue-fluid homeostasis, as a tissue-drainage system. Recent studies also revealed the vital significance of this lymphatic vasculature for the metastatic spread of tumor cells.

In the last decades, the wide-ranging research in the field of tumor-derived angiogenesis led to the identification of several angiogenic targets that can be effectively blocked in order to prevent the formation of new blood vessels in tumors, starving them of oxygen and nutrients and thereby preventing their growth.

As a result of these studies, several antibodies have been successfully developed and have demonstrated clinical benefit in treating several tumor types, such as bevacizumab (Avastin), which is based on the inhibition of vascular endothelial growth factor (VEGF) that induces endothelial cell proliferation, migration, and differentiation.

However, new research and clinical evidence suggests that tumors treated with this antiangiogenic approach may ultimately develop resistance to therapy and exhibit a progression to greater invasiveness. Therefore, there is an urgent need to explore other angiogenic targets that can be used therapeutically, such as the one validated by CNIO researchers in this study.

Related Links:
Spanish National Cancer Research Center