Glioblastoma or GBM is the aggressive cancer that occurs in the brain or spinal cord. While it can appear in people at any age, GBM typically occurs more often in older adults. Current treatments can slow progression of the cancer or sometimes reduce symptoms, but there is no known cure. Even now, GBM is difficult to treat at all.
A new study has lead scientists to believe they may have found a breakthrough in GBM treatments by reverse engineering the stem cells in the cancer. Scientists at the University of Toronto, University of Calgary, and The Hospital for Sick Children (SickKids) have published their findings in Cell Reports about their breakthrough using the CRISPR-Cas9.
What Is CRISPR-Cas9?
CRISPR stands for clustered regularly interspaced short palindromic repeats and is a family of DNA sequences in the genomes of bacteria. The Cas9 is the CRISPR associated protein 9 and is an enzyme using the CRISPR sequence as a guide to understand and remove certain strands in the DNA. Put together, the two become the CRISPR-Cas9 which is basically a technology that can edit the genes inside organisms. While we have other means of genetic manipulation, this is so far the easiest and precise method.
It can be happily reported that gene manipulation as we know it for now is an uncontroversial topic. Genetic changes are all about editing the somatic or non-reproductive cells rather than germline or reproductive cells. Because germline cells are the ones passed to a new generation, there is interest in getting involved with editing those as well but also ethical implications to consider. As of now, editing germline cells is illegal in most countries, including the United Kingdom.
How It Works
The Cas9 enzyme uses a piece of RNA to be its guide along the sequence. The guide is intentionally designed to bind to a specific sequence of DNA by having bases that compliment only the target. The Cas9 follows the guide RNA and severes the DNA strand. The cell then knows the DNA is damaged and tries to repair it. Scientists use the repair to their advantage and introduce changes or mutations to the cell and, subsequently, the DNA.
Bacteria work similarly. They have a natural gene editing system already built-in that responds to viruses. The bacteria takes out part of the virus’ DNA and keeps it so the virus can be recognized at a later time and defended against. This is how immunities work. Scientist have simply turned this system around to be used in animals and humans with more intentional purposes.
What CRISPR-Cas9 Does for GBM
With 10 patient-derived GBM cultures, the research time used CRISPR ‘cell fitness screens’ to take a closer look. They found particular genes in the cancer stem cells responsible for the cells to survive and grow, which were important to tumor progression. The use of the genes in the stem cells were a new discovery.
Dr. Stéphane Angers, the co-principal investigator of the study and Professor at the Leslie Dan Faculty of Pharmacy in the University of Toronto, is a CRISPR specialist. Angers said that, “In order to effectively target these cells, having a comprehensive view of the genes controlling the growth programs is critical. If you know which genes are necessary for these cells to survive and proliferate, you can then look at ways to attack of block these genes and stop tumor growth in its tracks.”
Results of the Study
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Thanks to the screening with CRISPR-Cas9, scientists found that adult GBM cells depend on the same genes used in brain development for infants and young children. This was found by going through the 20,000 genes in each of the 10 samples to discover their identity and worth. The study, using this data and technique, was able to provide a lot of new information for the research community to create new treatment strategies.
One of the genes they found in the GBM stem cells was DOT1L. This gene was discovered to be necessary to tumor persistence in seven out of the 10 cultures they studied. Dr. Samuel Weiss of the Cumming School of Medicine in the University of Calgary used a drug that’s currently used for treating leukemia on the gene. The drug was able to inhibit DOT1L production in GBM stem cells and slow the growth of tumors.
Angers went on to say, “We found that blocking this specific protein in this particular form of brain cancer reduced tumor growth and resulted in longer survival in the preclinical model. This is promising because it uncovered a biological process, not previously suspected to be implicated in glioblastoma, for which a small molecule drug already exists.”
What This Means for Current GBM Patients
Unfortunately, not much can be garnered right now for current patients with GBM. This discovery can lead to more treatment options for both GBM and other diseases, but the options are all being considered right now instead of being put into practice. There’s still a lot of studying to be done with this new technology and what we’re finding while using it.
Graham MacLeod of the Angers lab and co-first author of the study said that just knowing about genetic mutations isn’t enough. “That is a static picture of cancer. We are learning that we need to better understand the blueprint of how this cancer functions and what specific genes fuel tumor growth in order to attack it.” While correct, the new information about the mutations is helping to pave the way to better treatments and, someday, a cure.
The Future of Genetic Modifications
The CRISPR-Cas9 still has a lot yet to do. This study conducted just on GBM stem cells is actually broad enough to make waves throughout the scientific and medical communities. Finding so much information from tumor cells in the brain creates a lot of different categories for future researchers to look through for their own studies and theories.
So a cure for GBM may seem bleak right now, there is hope to take away from this. Not only are people continuing to research and learn about the cancer everyday, but scientists are also finding enough information to help in other projects, as well. In time, better treatments will be found, but the goal right now is to learn as much as we can to get to a cure faster.
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