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Molecular strategies for the treatment of malignant glioma—genes, viruses, and vaccines

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Abstract

The standard treatment paradigm of surgery, radiation, and chemotherapy for malignant gliomas has only a modest effect on survival. It is well emphasized in the literature that despite aggressive multimodal therapy, most patients survive approximately 1 year after diagnosis, and less than 10% survive beyond 2 years. This dismal prognosis provides the impetus for ongoing investigations in search of improved therapeutics. Standard multimodal therapy has largely reached a plateau in terms of effectiveness, and there is now a growing body of literature on novel molecular approaches for the treatment of malignant gliomas. Gene therapy, oncolytic virotherapy, and immunotherapy are the major investigational approaches that have demonstrated promise in preclinical and early clinical studies. These new molecular technologies each have distinct advantages and limitations, and none has yet demonstrated a significant survival benefit in a phase II or III clinical trial. Molecular approaches may not lead to the discovery of a “magic bullet” for these aggressive tumors, but they may ultimately prove synergistic with more conventional approaches and lead to a broadening of the multimodal approach that is the current standard of care. This review will discuss the scientific background, therapeutic potential, and clinical limitations of these novel strategies with a focus on those that have made it to clinical trials.

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Authors and Affiliations

  1. Division of Neurosurgery, Duke University Medical Center, Durham, NC, USA

    Lee A. Selznick, Matthias Gromeier, Allan H. Friedman & John Sampson

  2. Division of Neurosurgery, The Ottawa Hospital, Ottawa, Canada

    Mohammed F. Shamji

  3. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Mohammed F. Shamji

  4. Duke University School of Medicine, Durham, NC, USA

    Peter Fecci

  5. 2616 Erwin Road, #1416, Durham, NC, 27705, USA

    Mohammed F. Shamji

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  1. Lee A. Selznick
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Michael Weller, Zürich, Switzerland

“Molecular strategies for the treatment of malignant glioma” are in some way as old as the first efforts to use radiation or drugs in addition to surgery to improve patient outcome compared with surgery alone. These strategies were introduced into the clinic and were used with success, although it remained unclear what the precise molecular target was. For instance, molecular features almost certainly determine in part which tumors show prolonged local control in response to radiotherapy and which tumors progress even during this treatment. Moreover, although MGMT promoter methylation is now our first convincing molecular predictor of response to a meaningful type of medical treatment, chemotherapy with temozolomide, this marker was identified by retrospective analysis only, and the pivotal EORTC NCIC did not pursue the goal to demonstrate the predictive value of MGMT promoter methylation.

In contrast, as outlined in the present review article, the experimental clinical approach to malignant glioma has undergone tremendous changes in the last decade. We now hope that we are increasingly able to design molecular treatments a priori once we have the opportunity to examine tissue as well tissue cultures derived from this material. The idea behind this is to enrich study populations with patients most likely to benefit from a given treatment. For instance, molecular characterization of kinase pathways activated in a given tumor may be necessary to identify a subgroup of patients responsive to old and novel kinase inhibitors. Although the number of novel approaches to malignant glioma is steadily increasing, Selznick and colleagues still undertook the admirable effort to provide a broad overview about what they feel are the most promising concepts beyond surgery, radiotherapy and classic genotoxic chemotherapy. They focus on gene therapy including apoptosis signaling and classical suicide gene therapy, oncolytic viruses, and vaccines, and restrict themselves to approaches close to or already in the clinic. They aptly stress that none of the current treatment approaches alone may lead to a breakthrough in the treatment of malignant gliomas, but that intelligent combination approaches must be looked for. They have provided us with a very helpful overview about the current concepts of treatment that are close to stand or fall upon their first application in man.

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Selznick, L.A., Shamji, M.F., Fecci, P. et al. Molecular strategies for the treatment of malignant glioma—genes, viruses, and vaccines. Neurosurg Rev 31, 141–155 (2008). https://doi.org/10.1007/s10143-008-0121-0

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