Attacking Cancer Cells With A Zone Of Resistance

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Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 26 Sep 2008 - 0:00 PST

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A new study published in the journal Molecular Therapy reports on a new way to fight brain tumors using genetic therapy. Researchers from the Massachusetts General Hospital (MGH) were able to introduce a cancer-fighting gene into normal mouse brain tissue near a tumor that prevented the tumor from spreading. The animal study is the first of its kind to test the feasibility this approach. The researchers ultimately induced mouse brain cells to secrete human interferon-beta, suppressing and eliminating human glioblastoma cell growth from nearby implanted cells.

Miguel Sena-Esteves, PhD (MGH Neuroscience Center) said that the team, "Hypothesized that genetically engineering normal tissue surrounding a tumor could create a zone of resistance - a microenvironment that prevents the growth or spread of the tumor." The study's senior author added that, "This proof of principle study shows that this could be a highly effective approach, although there are many additional questions that need to be investigated."

A deadly and common form of brain tumor, glioblastoma has not yet been significantly reduced in human clinical trials of gene therapies. This is partly due to patients' immune systems, which tend to target viral vectors that are desired in order to deliver cancer-eliminating genes. There also has not been efficient gene delivery - an individual patient's tumor is highly diverse from a cellular perspective as are tumor tumors from different patients. Finally, if anticancer protein expression can be induced successfully in tumor cells, protein production will drop as the tumor dies and cells will continue growing that did not receive the gene. In this current MGH study, researchers analyzed the concept of a stable and effective anti-tumor reservoir that would be formed by therapeutic gene expression in normal brain cells.

Human interferon-beta is a protein that is being tested against several cancer types. By using adeno-associated virus vectors that have effectively delivered genes to neurons in the brain (rather than vectors associated with immune reactions), the researchers pretreated immune-deficient mice and delivered a gene for human interferon-beta into the animals' brains. After two weeks, human glioblastoma cells were introduced into the brains of the mice in the same or adjacent areas of the brain. A test of tumor size four days later revealed that mice expressing interferon-beta had significantly smaller tumors compared to the control group mice that were pretreated with gene-free vector. Further, tumors completely disappeared from the brains of the gene-therapy-treated mice just two weeks after introduction of the glioblastoma cells.

In order to make sure that the anti-tumor results were produced by expression of interferon-beta in normal tissue, the researchers conducted several additional experiments. They noted the same tumor growth suppression when genes and tumor cells were injected into opposite side of the brains. Additionally, the investigators utilized a specialized vector that allows genes to be expressed only in neuronal cells and not the glial cells from which glioblastomas originate - this yielded similar results. This study's effectiveness is highlighted because tumor growth suppression and elimination were achieved with a single injection of the interferon-beta-encoding vector rather than several vector injections that have been used in other gene therapy studies with mouse models.

"These results are particularly important as we build on our understanding of the microenvironments that allow tumors to grow and spread," adds Sena-Esteves. "The therapeutic principle of genetically engineering normal brain tissue could be used to manipulate proteins required for that microenvironment, preventing tumors from migrating within the patients brain and escaping other therapies." This zone-of-resistance approach, he notes, could be used to treat other solid tumors as well.

The authors conclude: "Our results represent a new paradigm for GBM [glioblastoma multiforme] therapy, as well as other malignancies, based on AAV-mediated [adeno-associated virus] genetic engineering of normal tissue to manipulate the tumor microenvironment. Furthermore, the efficiency of tumor regression in the brain is currently unrivaled with existing preclinical GBM-therapy strategies using AAV vectors. This therapeutic approach could be translated into clinical trials by multiple injections of vector into the surrounding brain parenchyma during tumor re-section to create a zone of resistance to tumor recurrence."

Preventing Growth of Brain Tumors by Creating a Zone of Resistance
Casey A Maguire, Dimphna H Meijer, Stanley G LeRoy, Laryssa A Tierney, Marike LD Broekman, Fabricio F Costa, Xandra O Breakefield, Anat Stemmer-Rachamimov and Miguel Sena-Esteves
Molecular Therapy (2008). Vol. 16: 1695-1702
doi:10.1038/mt.2008.168
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