Study identifies biomarker that safely monitors tumor response to new brain cancer treatment
Gene therapy technique developed in animal model by Cedars-Sinai research team uses immune cells to attack glioblastoma multiforme
A specific biomarker, a protein released by dying tumor cells, has been identified as an effective tool in an animal model to gauge the response to a novel gene therapy treatment for glioblastoma mulitforme. The finding, reported in Clinical Cancer Research, paves the way for a Phase 1 clinical trial expected to begin in late 2009.
The gene therapy is a two-pronged strategy devised by scientists at the Cedars-Sinai Board of Governors Gene Therapeutics Research Institute. It uses a genetically engineered, harmless virus to deliver a combination of proteins and a drug to kill tumor cells, which triggers an ongoing immune response against malignant brain tumors cells. The Cedars-Sinai team led by Pedro R. Lowenstein, M.D., Ph.D., director of the Board of Governors Gene Therapeutics Research Institute, and Maria G. Castro, Ph.D., co-director of the Institute, developed this gene therapy strategy during 10 years of laboratory research.
"Using this therapy, we have shrunk and completely eliminated very large brain tumors in animals and have trained their immune systems to develop memory so that recurrent tumors are also destroyed," said Castro, principal investigator of the study. "The biomarker identified in this study will help us determine the effectiveness of the therapy in patients with glioblastoma multiforme."
In this study, the researchers identified the most effective and least toxic combination of therapeutic agents that would offer the best results. They found that a protein released by dying tumor cells may be used as a "biomarker" to gauge the effectiveness of treatment. This protein, called "high mobility group box 1" (HMGB1), regulates gene expression in healthy cells by binding to the cells' DNA. When cancerous cells are killed, however, HMGB1 is released into the general blood circulation. This research shows that measuring the levels of HMGB1 in the blood could be a non-invasive but essential way to monitor the effectiveness of cancer therapeutics in patients. These findings will be used to fine-tune the therapy as it enters the Phase I clinical trial.
In the technique devised by Castro and Lowenstein, one of the proteins (the immune stimulatory cytokine Flt3L) attracts dendritic cells from bone marrow into the tumor while another protein (thymidine kinase) and the antiviral drug gancyclovir combine to kill tumor cells. The dying tumor cells are detected by the newly recruited dendritic cells, which initiate the anti-tumor response. The biomarker identified in this study is a result of the ongoing battle between the T cells and the tumor cells. As such, the biomarker will be a useful direct reporter of the ensuing fight to kill the tumor.
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Topic world Gene therapy
Genetic diseases once considered untreatable are now at the center of innovative therapeutic approaches. Research and development of gene therapies in biotech and pharma aim to directly correct or replace defective or missing genes to combat disease at the molecular level. This revolutionary approach promises not only to treat symptoms, but to eliminate the cause of the disease itself.
Topic world Gene therapy
Genetic diseases once considered untreatable are now at the center of innovative therapeutic approaches. Research and development of gene therapies in biotech and pharma aim to directly correct or replace defective or missing genes to combat disease at the molecular level. This revolutionary approach promises not only to treat symptoms, but to eliminate the cause of the disease itself.
