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Scientists find key driver for treatment of deadly brain cancer

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Glioblastoma multiforme is a quite a deadly form of brain cancer. Typically, the maximum lifespan of person with this form of brain cancer after diagnosis is 15 months, if given the best care. Researchers at the Salk Institute have discovered a crucial key to how these tumor cells proliferate so fast and also how to use the finding into a target for cancer treatment. The details of the study finding were published recently in the journal Science Advances.

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Inder Verma, professor in the Salk Institute’s Laboratory of Genetics and senior author of the paper remarked that there has been practically no improvement in treatment outcome for this disease for years. Years of study have confirmed the fact that even if a surgeon removes 99.99 percent of a glioblastoma multiforme tumor, what is left grows again into more tumor.

Verma’s team focused on a transcription factor called nuclear factor kB (or NF-kB) to study how glioblastoma multiforme spreads. The function of a transcription factor which is a protein is to bind to DNA and control the gene expression for a particular set of genes. NF-kB activity in a cell can be triggered due to ultraviolet and ionizing radiation, immune proteins (cytokines) and DNA damage. A number of tests were carried out by Verma and his team to show how overzealous NF-kB activity pushed the cancer cells to proliferate, and how stopping NF-kB slowed cancer growth and increased survival.

Dinorah Friedmann-Morvinski, currently a researcher in the department of biochemistry and molecular biology at Tel Aviv University in Israel and first author of the paper said that their experiments confirmed that NF-kB is required for the cancer cell to proliferate. We have also found a way to ameliorate the tumor to increase lifespan.

The team of researchers began their experiments on a mouse model of glioblastoma multiforme and used genetic tools to manipulate cells into shutting down NF-kB activity in two ways. One was to ramp up the presence of a protein called IkBaM, which inhibits NF-kB activity and second was to eliminate an enzyme that increases NF-kB activity. When the NF-kB activity was reduced, the tumor growth slowed and mice lived significantly longer. These genetic experiments however aren’t a feasible treatment in humans.

Verma said that they thought of manipulating the system using pharmacology rather than genetics. The tumor microenvironment is one reason why glioblastoma multiforme comes back so quickly after surgery. It seems the tumor changes the environment of its nearby tissues to help cancer cells thrive. So, Verma and colleagues decided to treat the brain tumors in a way that also changed the tumor microenvironment. The scientists fed mice a peptide (called NBD) that is known to block NF-kB activity when NF-kB is triggered by cytokines (proteins produced by the immune system). The NBD peptide can travel across the central nervous system, and successfully penetrate glioblastoma tumor cells. Treating mice with the NBD peptide doubled their typical survival time compared to mice that didn’t get the NBD peptide.

Verma remarked that they could increase survival time from one month without treatment to three months with treatment and that achievement is something significant. However, this step is not a complete solution as peptide treatment eventually causes toxicity, particularly in the liver. So, another way to slow NF-kB activity needs to be explored. Reducing NF-kB activity is tricky because as it has many important roles like regulate cell survival, inflammation and immunity, etc.

Verma said that in order to be more selective in the treatment, our aim is to find the handful of genes that directly affect tumor growth. On further experimentation, the researchers found that the gene Timp1 is influenced by NF-kB activity. When this gene is targeted in treatment, it also slowed tumor growth and increased survival time in mice by a few months.

Friedmann-Morvinski remarked that in the future they would focus on ways to reduce the toxicity of anti-NF-kB drug. Also, they would work to identify treatments that target NF-kB activity in a safe and effective way.