A recent study by National Cancer Institute predicts that the societal costs attributed to brain cancer will increase by 0.83 billion dollars by the year 2020 [1
]. This increase in cost is predicted in spite of new medical and therapeutic discoveries, thus supporting the urgent need for more cost effective and efficacious therapies. Peptides are receiving increased attention as therapeutic agents, due to their high binding specificity and versatility to be modified as targeting or carrier molecules [2
]. Peptides are being increasingly used in therapeutic applications for multiple diseases including cancer. One example under development for multiple cancers is Cilengitide, an RGD pentapeptide that inhibits αν
]. Peptides with anti-angiogenic activity [7
] are of particular interest due to the role for angiogenesis as a process central to the development and malignant progression of multiple malignancies [9
]. Glioblastoma multiforme (GBM), is one of the most common and aggressive brain tumors with a dismal median survival of 12–15 months. Invasive gliomas such as GBM are characterized by insidious infiltration of tumor cells into surrounding brain and robust tumor angiogenesis that together cause tumor growth, morbidity and death [10
]. The current standard of care for GBM consists of surgical resection of primary tumor, concurrent adjuvant chemotherapy and radiation followed by additional adjuvant chemotherapy. Bevacizumab, an antibody against vascular endothelial growth factor (VEGF) received expedited approved by FDA (May 2009) for treatment of patients with progressive disease following prior therapy. Several studies have demonstrated that Bevacizumab leads to an extension of progression free survival without obviously prolonging the overall survival. The limitations of Bevacizumab and other emerging anti-angiogenic strategies may relate in part to the compensatory induction of an invasive glioma phenotype and growth pattern. Thus more effective therapies using agents with multiple mechanisms of action (e.g. anti-angiogenic + anti-invasion) are needed [9
In this study we investigate the application of two anti-angiogenic peptides belonging to different classes in application to glioma therapy. Targeting the disease from different perspectives, angiogenic and tumorigenic, along with inducing these effects via different receptors and thus affecting different signaling and molecular pathways could lead to an effective multimodal therapeutic approach.
Chemokines are cytokines involved in directed migration of leukocytes and are classified in four major classes, CXC, CC, C and CX3C. Amongst these, chemokines belonging to the CXC family have been shown to be involved in tumor angiogenesis [13
]. We previously showed that peptides derived from this family are strongly active in inhibiting the migration and proliferation of human umbilical vein endothelial cells (HUVEC) [15
] and also are capable of inhibiting tumor growth in a breast cancer xenograft model [17
The other peptide that we investigate in this study is derived from collagen IV and it interacts with integrins, specifically with the αV
integrins which are overexpressed on both tumor endothelial and cancer cells [16
]. We previously characterized the effect of this peptide on endothelial cells and found that it is capable of strongly inhibiting endothelial cell proliferation and also inhibits migration (80% inhibition at 30 μg/ml) [19
]. This peptide and a homologous mimetic peptide were shown to inhibit tumor growth in breast cancer [17
] and lung cancer [22
] xenograft models.
In this study we focus on the characterization of the activity of the peptides on glioma cells and test their activity in vivo in glioma xenografts using U87 cells.