Inhibition of a major enzyme that controls a large network of proteins that is important in cell division and growth paves the way for a new class of drugs that can stop glioblastoma, deadly brain cancer, from growing.
Researchers at the Princess Margaret Cancer Center, the Hospital for Sick Children (SickKids) and the University of Toronto have shown that chemical inhibition of the enzyme PRMT5 can suppress the growth of glioblastoma cells.
Inhibition of PRMT5 resulted in cell senescence, similar to what happens to cells as they age as cells lose their ability to divide and grow. Cell senescence can also be a powerful tool for tumor suppression, preventing the unstable separation of cancer cells.
The results of the study are published in Nature Communication on February 12, 2021, with the lead author being the Postdoctoral Fellow Dr. Patty Sachamitr, SickKids and the University of Toronto, and senior authors Drs. Panagiotis Prinos, Principal Research Partner, Consortium of Structural Genomics, University of Toronto, Principal Scientist Cheryl Arrowsmith, Princess Margaret, and Principal Scientist and Neurosurgeon Peter Dirks, SickKids.
The researchers are part of the Stand Up To Cancer Canada Dream Team that targets brain tumors that have the worst outcomes, such as glioblastomas. By combining extensive and in-depth research experience, clinical strengths, and unparalleled partnerships, the researchers hope to accelerate new treatments to treat some of the most difficult cancers.
Currently, the prognosis for glioblastoma remains very poor, with less than 10% of patients living longer than five years. Conventional treatments are severely limited.
Although inhibition of PRMT5 has previously been proposed as a means of targeting brain cancer and other cancers, this strategy has not been tested in a large cohort of stem cells derived from patient tumors that have gas-cell characteristics, cells which is at the root of glioblastoma growth.
“We used a different strategy to stop cancer cells from expanding and spawning new tumors,” says Dr. Arrowsmith, who also manages the University of Toronto’s site of the Consortium for Structural Genomics -national, public-private partnership with laboratories around the world, accelerating the discovery of new medicines through open science.
“By inhibiting a single protein, PRMT5, we were able to effect inhibition of proteins involved in cell division and growth. The traditional way to stop cell division is to blocking a single protein. This gives us a new foundation for the future development of novel, more detailed therapies. “
“This strategy also has the potential to overcome the genetic differences seen in these tumors,” said Dr. Dirks, who led the pan-Canadian team. “By focusing on processes involved in all patient tumors, which are also essential for tumor gas cell survival, we will step up the challenges of individual patient tumor variability to find treatments that could be more broadly appropriate. “
Adverse glioblastoma outcome could be explained, at least in part, by tumor-initiating cancer gas cells, which were revealed by Dirks’ lab to stimulate tumor growth and resistance to treatment. movement. Novel therapeutic strategies are urgently needed to target these cancer stem cells, as well as large tumor cells.
In this study, researchers tested a group of new experimental small molecules designed to specifically inhibit the development of key cell enzymes and analyzed by the Consortium of Structural Genomics to see whether the growth of glioblastoma brain tumor cells was inhibited in the laboratory. The brain tumor cells were isolated from patient tumors and grown in the laboratory in a way that preserved the specific properties of cancer stem cells.
They found that certain molecules – a precursor to true therapeutic drugs – inhibited the same enzyme, PRMT5, inhibiting the growth of a large proportion of these cancer stem cells that came from patients. Many conventional drugs do not destroy cancer cells, which may be why many cancers recur after treatment.
But they also warn that real treatments for patients are many years away, and that they need to develop and test clinically appropriate and safe versions of PRMT5 inhibitors that access the brain.
The researchers also studied the molecular characteristics of glioblastoma cells derived from patients by comparing those who responded well to those who did not respond as well. They found a different molecular signature for the corresponding tumor cells. In the future, this could lead to specific tumor biomarkers, which may help identify those patients who are best treated with this new class of drugs.
Currently, we have too few medications to choose from to produce a thorough treatment for many patients. We need basic research to better understand the mechanism of drug action, particularly in the context of patient samples. This is what will help us develop the right drugs to give the right patients to treat their specific tumors. “
Dr. Cheryl Arrowsmith, Senior Specialist
Source:
University Health Network