Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find that combined gene therapy eliminates glioblastoma multiforme in lab studies

15.08.2005


Despite aggressive treatment, glioblastoma multiforme (GBM) – the most common and deadly of brain cancers – usually claims the lives of its victims within six to 12 months of diagnosis. Because GBM is so aggressive, the disease has been the target of a number of laboratory and clinical studies investigating the effectiveness of gene therapy to deliver novel therapies to the brain. In laboratory studies, this type of gene therapy has proved almost completely effective. But in clinical trials, it has had limited effectiveness.



To overcome these limitations, researchers at Cedars-Sinai Medical Center developed a large brain tumor model in laboratory rats that would more accurately predict the outcome of gene therapies in patients. In addition, they tested a genetically engineered virus to deliver two proteins directly to the brain. Their findings, reported in the August 15th issue of the journal Cancer Research, show that the majority of rats bearing large tumors were still alive six months after combined treatment with two proteins: RAdTK, a protein that kills cancer cells, and RAdFlt3L, which stimulates immune or dendritic cells in the brain.

"Our study shows that GBM tumors were completely eliminated in lab rats, likely because the two proteins increase the production of fully mature immune cells within the brain," said Maria Castro, Ph.D., co-director of the Gene Therapeutics Research Institute at Cedars-Sinai Medical Center and the senior author of the study. "This suggests that combined RAdFlt3L and RAdTK gene therapy may ultimately provide an effective treatment for patients undergoing clinical trials with GBM."


GBM tumors derive from brain astrocytes, a cell that normally supports and nurtures the brain’s neurons. GBM grows quickly, often becoming very large before any symptoms are experienced. Once GBM is diagnosed, conventional treatment begins with surgery to remove as much of the tumor as possible and is then followed with radiation and/or chemotherapy to slow progression of the disease. But despite aggressive treatment, the tumors recur and patients usually die within a year’s time.

To find another way to more effectively treat GBM, scientists have begun investigating the use of gene therapy to deliver novel therapeutic agents directly to the brain. Typically, these studies have tested the use of the suicide gene from the herpes simplex virus to develop a gene therapy approach that kills cancer cells in the presence of the antiviral drug – gancyclovir. In laboratory studies, this type of gene therapy has proved almost 100 percent effective. But in clinical trials, it has had limited effectiveness, suggesting that the tumor mass is too large for the gene to effect long-term.

"Because we haven’t seen the same positive results with gene therapy in clinical trials that we’ve seen treating GBM in laboratory rats, we realized that we needed to design a better model that more closely mimicked these tumors in patients," Castro said. "We also wanted to test whether a combined gene therapy strategy using proteins known to kill cancer cells or promote an immune response would work to eliminate these larger tumors in the rats."

Gene therapy is an experimental treatment that uses genetically engineered viruses to transport genes and/or proteins into cells. Just like a viral infection, the viruses work by tricking cells into accepting them as part of their own genetic coding. To make them safe, scientists remove the genetic viral genes that cause infection and engineer them so that they stop reproducing after they have delivered the therapeutic genes.

In this study, the researchers first developed a large GBM tumor model and implanted them in rats, allowing the tumor to grow for 10 days, when they were at their largest. Secondly, the investigators tested the effectiveness of various gene therapies used in combination or individually to see whether they would shrink or eliminate tumors.

To determine whether the size of the tumor significantly affected survival, the researches implanted both large and smaller GBM tumors in rats. The investigators then treated rats bearing GBM tumors with single or combined gene therapies (RAdTK and/or RAdFlt3l), or a saline placebo, as a control. They found that RAdTK treatment was 100 percent effective when delivered into small tumors, but only 20 percent effective when injected into large tumors. RAdFlt3L, on the other hand, was 60 percent effective if delivered into small tumors, but failed completely if injected into the large tumors. But when both RAdTK and RAdFlt3l were given in combination, the investigators found 70 percent of rats were still alive after six months of treatment and that the large GBM tumors had completely disappeared or shrank significantly.

"Just as with patients, our results emphasize that tumor size at the time of treatment is critical to predict clinical outcome," said Pedro Lowenstein, M.D., Ph.D., director of the Gene Therapeutic Research Institute at Cedars-Sinai. "Our model reproduces more closely the human disease condition where tumor size at the time of treatment determines how well the patient will respond to therapies."

"Our results show for the first time, that we could elicit a potent and stable anti-tumor immune response in the brains of rats bearing large GBM tumors," Castro said. "In these pre-clinical studies, combined gene therapy treatment with RAdTK and RAdFlt3L dramatically increased survival, without adverse immune reactions in the brain."

Kelli Hanley | EurekAlert!
Further information:
http://www.cshs.org
http://www.csmc.edu

More articles from Life Sciences:

nachricht Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>