According to the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, every year in the United States, there are more than 40,000 new cases of, and deaths caused by, cancers of the brain and nervous system.
Of these, glioblastoma is one of the most aggressive types of brain cancer, and it has a very poor survival rate, as per the Genetic and Rare Disease Information Center.
Researchers have found that a particular population of cells within the main tumor, called "glioma stem cells," are responsible for the tumor's formation, its resistance to chemotherapy and radiotherapy, and its high recurrence rate following treatment.
Dr. Ichiro Nakano, from the University of Alabama at Birmingham, and Dr. Maode Wang, from Xi'an Jiaotong University in China - in collaboration with colleagues from both institutions - have now identified the mechanism that keeps glioma stem cells from transforming.
The researchers have also designed a new molecule inhibitor, allowing them to test the newly discovered mechanism as a therapeutic target in glioblastoma. They report their findings in The Journal of Clinical Investigation.
Enzyme responsible for tumor resilience
The study was prompted by the researchers' observation that OTS167, a cancer cell inhibitor, failed a clinical trial. This discovery led Dr. Nakano and his team to look into the mechanism that allows glioblastoma to withstand this inhibitor.
Their investigation revealed the evolution of NEK2, an enzyme that plays a role in regulating cell division, following treatment with OTS167 in the case of glioblastoma.
NEK2 is crucial in glioma cell cloning in vitro, and in the growth and endurance of the tumor, as observed in vivo.
In the experiments conducted throughout the study, it was noted that NEK2 binds to another enzyme called EZH2, which is responsible for preventing the system from suppressing malign tumors.
The binding stabilizes EZH2, allowing cancerous growths to proliferate. The researchers explain that blocking this interaction is key.
"Disrupting the NEK2-EZH2 interaction in cancer cells has the potential to target their cancer stem cell compartment. This strategy may serve as a new therapeutic approach for recurrent tumors and a subgroup of primary tumors."
EZH2 is not confined to glioblastoma; the expression of the gene that encodes the enzyme was also noted in other types of cancer, and its over-expression often leads to negative treatment outcomes.
The researchers also investigated the links between the EZH2 and NEK2 genes in tumorous brain tissue collected from 44 glioblastoma patients.
They found a connection between NEK2 and EZH2 expression, both of which were associated with poor patient outcomes.
Researchers design therapeutic inhibitor
Where therapy had not succeeded, high levels of NEK2 were observed in the recurrent tumors. Following these discoveries, Dr. Nakano, Dr. Wang, and their teams designed a new drug called CMP3a.
This drug is set to target NEK2 by selectively inhibiting its activity in glioma stem cells. It was able to hinder glioblastoma growth, as the scientists observed both in vitro and in vivo.
Regular astrocytes - which are star-shaped glial cells that can also serve as the "breeding ground" for glioblastoma tumors - demonstrated resistance to CMP3a, which confers even more reliability to this inhibitor.
Paired with radiotherapy, CMP3a treatment was even more effective in reducing the growth of glioblastoma in vitro.
The researchers are currently testing the therapeutic dosage of CMP3a in the treatment of glioblastoma and other types of cancer, hoping to develop a better method of treating the most aggressive forms.
"We are hopeful to add this drug candidate to our list of clinical trial protocols for glioblastoma in a year or two," concludes Dr. Nakano.