Research Project
9628540
Effective treatment of glioblastoma (GBM), the most common and most lethal human brain tumor, represents one of the most formidable challenges in oncology. Despite the use of surgery, radiation therapy and chemotherapy, the prognosis for patients with GBM remains poor. It is the infiltrative nature of these tumors that eliminates the possibility of curative surgical resection. Conventional DNA-damaging chemotherapies may exhibit limited duration of efficacy because GBM cells are proficient at repairing DNA damage, leading to drug resistance. CD97 is a cell-surface protein that is significantly upregulated in GBM and overexpression confers an invasive phenotype to glioblastoma cells and is associated with decreased survival of GBM patients. Because of this, CD97 is an attractive therapeutic target for GBM. The extracellular region of CD97 contains binding sites for a number of cellular ligands, one of which is CD55, the decay accelerating factor for complement, also known as DAF. We have produced fusions of human DAF with human IgG1 Fc and have demonstrated a strong neutralizing interaction between DAF-Fc and CD97, with resulting inhibition of GBM migration in culture and a profound antibody-dependent cellular cytotoxicity (ADCC) reaction against GBM cells. We therefore propose developing DAF-Fc as a GBM therapy. We will produce, using our plant expression system, additional forms of DAF-Fc, modified to have improved ADCC activity and be retained more efficiently in the brain. We will evaluate the ability of these DAF- Fc variants to bind to purified CD97 and CD97-expressing GBM cells, and to kill GBM cells in ADCC assays. We will also compare the ability of the DAF-Fc variants to inhibit GBM cell migration, proliferation, complement activation, and angiogenesis. We will compare the in vivo activity of DAF-Fc variants against patient-derived human glioblastoma intracranial xenografts in immunodeficient mice, as well as verify the lack of toxicity of DAF-Fc treatment. We anticipate that these studies will validate our hypothesis regarding the impact of CD97 on GBM biology and will eventually impact the poor prognosis faced by patients with this devastating cancer.
