Glioblastoma is a particularly aggressive form of brain tumor, with a median survival rate of 10–12 months.
Part of the reason why glioblastomas are so deadly is that they arise from a type of brain cell called astrocytes.
These cells are shaped like a star, so when the tumors form they develop tentacles, which makes them difficult to remove surgically.
Additionally, the tumors advance rapidly. This is because astrocytes provide support to neurons and control the amount of blood that reaches them; so, when tumors form, they have access to a large number of blood vessels, helping cancerous cells to grow and spread very quickly.
Another reason that glioblastomas are so difficult to treat is their high rate of recurrence. This is partly due to a subpopulation of cells contained in the tumor called glioma stem cells (GSC) — a type of self-regenerating cancer stem cell that controls the growth of tumors.
Subhas Mukherjee, Ph.D., a research assistant professor of pathology at the Northwestern University Feinberg School of Medicine in Chicago, IL, and his colleagues have been studying the behavior of these cells for a few years.
Building on this previous research, Mukherjee and team have now found that these cells contain high levels of an enzyme called CDK5.
Blocking this enzyme, the researchers show in their new study, stops glioblastomas from growing and inhibits the self-regenerating capabilities of GSCs.
The findings were published in the journal Cell Reports.
CDK5 inhibitor stops tumor growth
Previous research using a Drosophila fly model of brain tumors conducted by Mukherjee and team revealed that silencing the gene that encodes CDK5 decreased tumor size and the number of GSCs.
Further genetic screening in humans with glioblastoma revealed that these people also had high levels of the CDK5 enzyme.
Mukherjee further details the research process, saying, “We started running tests in our lab and found CDK5 promotes a high level of stem-ness in cells, so they proliferate and grow more.”
“We isolated the cells that were most stem-like, and found that they have a high level of CDK5 compared to ones that are less stem-like.”
Next, the researchers applied a CDK5 inhibitor to human glioblastoma cells. This stopped the tumors from growing and caused GSCs to lose some of their stem-ness, making it harder for them to regenerate.
The researchers also tested the efficacy of this enzyme-blocker on the three main subtypes of glioblastoma: the neural, classic, and mesenchymal subtypes.
Of these, the latter subtype was shown to have lower levels of CDK5, so in the future, this new approach may not benefit patients with mesenchymal glioblastoma as significantly.
New compound may halt tumor recurrence
Mukherjee comments on how his and his team’s findings may change therapeutic practices for the treatment of glioblastoma:
“The mortality rate for glioblastoma has only moderately changed in last 30 years,” he says. “The current drug, temozolomide, is somewhat effective when the tumor recurs — and one of the major problems with glioblastomas is they tend to come back.”
But, using the CDK5 inhibitor in combination with this chemotherapy drug might hinder tumor growth and stop them from returning.
“The idea is to kill the remnants and glioma stem cells after chemotherapy,” Mukherjee says. “Those are the cells that persist and cause recurrence.”
The CDK5 inhibitor — called CP681301 — can cross the blood-brain barrier, he explains, and the results of this study suggest that the compound is ideal for creating new drugs.
Mukherjee is already working on designing such a drug and is hopeful that the process will be quite speedy. “We will hopefully generate some models and start testing within a few months,” says the researcher.
Source: Read Full Article