Gene Therapy and Targeted Toxins for Glioma

Abstract

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted, this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.

Brain Tumor Imaging: Live Imaging of Glioma by Two-Photon Microscopy

“…Despite progress in treating primary tumors in the periphery, tumors that initiate in the central nervous system (CNS) or that preferentially migrate from peripheral primary or secondary metastatic sites into the brain remain refractory to treatment (King et al 2005;Lin et al 2004;Weil et al 2005). Neurons and the supporting glial cells of the brain create a distinct microenvironment for primary brain tumors, and metastastic tumor cells must adapt to this unique environment (Weil et al 2005).…”

“…Animal models that recapitulate all aspects of brain tumor pathogenesis are critical to improve our understanding of CNS tumors and to develop more effective therapies that inhibit their development. Glioblastoma is an invasive brain tumor with a high mortality rate, even with treatment (King et al 2005). The rat CNS-1 cell line is a widely used, well-characterized model of infiltrative glioma grown in nude mice.…”

Transposon-based interferon gamma gene transfer overcomes limitations of episomal plasmid for immunogene therapy of glioblastoma

“…Nevertheless, both adenoviral and SB vectors have been used to cause sustained tumor regression when more effective therapeutic genes are delivered. 2,3 SB offers an important advantage characteristic to viral vectors (i.e., long-term expression), whereas still retaining the amenability to large-scale manufacture that makes nonviral vectors attractive.…”

“…In contrast to nonviral vectors, viral vectors have often facilitated sustained expression of antitumor proteins from a single administration in murine models. [3][4][5] A typical approach to overcoming the transient expression of nonviral gene transfer has been repeated administration, which has produced encouraging results in patients with metastatic melanoma 6 and renal cell carcinoma. 7 New approaches that allow sustained gene expression could potentially reduce the number of administrations required, and increase the efficacy of nonviral cancer gene therapy vectors.…”

“…3 Despite advances in surgery, radiation and chemotherapy, the prognosis for GBM patients remains dismal with a median survival of 15 months and 2-year survival rate below 27%. 8 Gene therapy has shown modest efficacy in GBM patients, 3,9,10 but curative therapy remains an elusive goal.…”