Tie Fu Liu

Combination fusion protein therapy of refractory brain tumors: demonstration of efficacy in cell culture.

Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and relative resistance to chemotherapy and radiation therapy. Novel agents that can kill multi-drug resistant tumor cells and reach tumor cells at distant sites in the brain are needed. One such class of agents is fusion proteins which consist of brain-tumor-selective peptide ligands fused to peptide toxins. The ligand directs the protein to the glioma cell surface; the peptide toxin is then internalized into the cell, translocates to the cytosol and catalytically inactivates protein synthesis leading to cell death. Fusion proteins are toxic to multi-drug resistant brain tumor cells. Because of the large molecular weight of these molecules, a unique delivery system has been developed – convection-enhanced delivery (CED). The method creates a bulk flow which supplements diffusion and achieves drug concentrations in the brain parenchyma orders of magnitude greater than by systemic administration. Patients with recurrent glioma treated with individual fusion protein CED have obtained clinical remissions lasting years. However, toxicities to normal brain have been observed and relapses ultimately occurred. To address the clinical need of these patients and improve upon the therapeutic index observed to date with single fusion protein CED, we generated a novel fusion protein DAB389EGF and tested it in combination with another active fusion protein, IL13PE38QQR. We observed potent glioma cytotoxicity with each fusion protein and synergistic toxicity with the combination. Further, brain tumor cells showed heterogeneous expression of individual receptors suggesting that the combination – DAB389EGF and IL13PE38QQR may show improved efficacy and should undergo further preclinical development for therapy of patients with relapsed high-grade gliomas.

Recombinant toxin DAB389EGF is cytotoxic to human pancreatic cancer cells

Few malignancies have frustrated the persistent efforts of the oncologist like pancreatic cancer. Pancreatic cancer is usually unresectable at the time of diagnosis because of metastasis or local extension. Despite the aggressive nature of this deadly disease, systemic treatment options are limited. Even the recent introduction of the deoxycytidine analogue gemcitabine does not extend median survival of responders beyond a year. Clearly, alternative, more effective regimens are needed for treating pancreatic carcinoma. In pancreatic cancer, there is overexpression of growth factors and growth factor receptors, including epidermal growth factor receptor (EGFR). Targeted toxins consist of a targeting polypeptide covalently linked to a peptide toxin. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). The authors have previously shown that DAB389EGF is selectively toxic to EGFR-overexpressing cells, including human brain tumour and lung carcinoma cell lines. Pancreatic adenocarcinoma should be responsive to this fusion protein based on its EGFR overexpression. However, the cytotoxic effect of DAB389EGF on human pancreatic carcinoma cell lines has yet to be explored. The authors describe preliminary data showing the potent cytotoxicity of DAB389EGF to human pancreatic carcinoma cell lines. Because of the nonspecific toxicity to liver and kidney (which possess EGFR) of systemic administration, they also propose a potential novel drug delivery system for direct toxin implantation into pancreatic tumours using endoscopic ultrasound guided fine-needle injection (EUS-FNI). Hopefully, the use of these targeted therapeutic approaches in combination with other modalities may further extend survival and quality of life in patients with pancreatic adenocarcinoma.