Recently, researchers at Northwestern University Medical School successfully prevented the growth of glioblastoma which was an invasive form of brain cancer by inhibiting an enzyme called CDK5. The related study has been published in the Journal of Cell Reports.
Dr. Subhas Mukherjee, the first author of this study and assistant professor of pathology, believes that the regulatory role of this enzyme in glioblastoma offers a new sight for improving current therapies.
Mukherjee said, ‘The death rate of glioblastoma has increased significantly in the past 30 years. When the tumor relapses, the current drug temozolomide can play a role in inhibiting, however, the main problem with glioblastoma is that it involves a high probability to recur.’
CDK5 is a protein kinase that is a class of enzymes that modify protein function and play a major role in the regulation of proteins and enzymes. Although CDK5 was previously thought to be involved in neurodegenerative diseases including Alzheimer's disease, until recently, researchers started to notice its relationship with glioblastoma.
The high recurrence of glioblastoma is caused by glioma stem cells. This kind of self-renewing cancer stem cell supports the growth of the tumor. Mukherjee began the research of glioma stem cells when he was studying the Post-doctoral degree at Emory University in the United States. He screened 29 Drosophila models of brain tumors, each with a single silent gene.
Mukherjee and his colleagues found that when the gene encoding CDK5 was turned off, tumors in the brain of Drosophila were reduced, and the number of cancer stem cells was also decreasing. In the human body, they analyzed genetic data from patients with glioblastoma who analyzed cancer genomic profiles and found that a large number of patients with glioblastoma also have high levels of enzymes. The Cancer Genome Atlas is a genetic database containing data from 11,000 cancer patients donated by the National Institutes of Health (NIH).
Mukherjee said, ‘We started running tests in the lab and found that CDK5 promoted high levels of stem cells in cells, so the cells proliferate and grow more. We isolated the cells that most closely resembled stem cells and found that they had higher levels of CDK5 than cells with lower levels of other stem cells.’
With the establishment of the growth-regulatory properties of CDK5, the researchers applied an experimental CDK5 inhibitor to human glioblastoma cells. They found that this inhibitor can prevent tumor growth and make the stem cells of cancer stem cells attenuate, and finally losing the ability of self-renew.
In addition, they found that only two of the three major glioblastoma types were highly able to express CDK5. This proves that patients with a third subtype (mesenchymal glioblastoma) will not be able to take advantage of CDK5 to inhibit tumor cell growth.
The researchers pointed out that the reduced cell interference, coupled with the specificity of the drug and its ability to cross the blood-brain barrier, making this method an ideal choice for therapeutic application. Currently, Mukherjee is working on developed an improved indigenous drug by cooperating with the Center for Molecular Innovation and Drug Discovery at Northwestern University. He claimed that it is possible to generate models and start testing in a few months.
Mukherjee predicts that this therapy can be used as a primary treatment option along with chemotherapy in the future. Preliminary data indicate that CDK5 is very important for tumor recurrence, so CDK5 inhibitors can act in two ways, that is preventing tumor growth and tumor recurrence respectively.
Mukherjee said: ‘Our idea is to kill residual cancer cells and glioblastoma stem cells which are always present and cause tumor recurrence after chemotherapy.’
Reference:
Mukherjee et al., CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells. 2018, Cell Reports 23, 1651–1664