A new Yale study has identified cancer-causing genes for a lethal brain cancer called glioblastoma, thanks to a newly developed mouse-based screening test.
Researchers at the Yale School of Medicine have used the CRISPR/Cas9 system — which allows researchers to alter the DNA sequence at specific points — to create a new and advanced mouse model for glioblastoma. Using this robust model, the researchers discovered a set of mutations that are responsible for driving cancer cell growth. Importantly, the study employed an adeno-associated virus to deliver a large library of glioblastoma gene mutations, allowing researchers to determine the progression of the disease as the genes competed in the brain. The study was published in the journal Nature Neuroscience on Aug. 14.
“Our model was different because healthy tissue turned into diseased tissue, whereas traditional models take diseased tissue and implant it into healthy tissue,” said Christopher Guzman, a lead author of the paper and graduate student in the Yale School of Medicine’s cancer systems biology laboratory. “We set out to reverse engineer the disease and uncover interactions between the components.”
Another exciting aspect of this study, according to Guzman, is the potential to apply this screening technology to other types of cancer. As long as AAV viruses can be produced to target certain cell types, this study can be replicated in an array of other cancers to figure out their driver mutations, he added.
Glioblastoma is one of the most deadly cancer types with patients living, on average, only 15 months after the initial diagnosis. Sidi Chen, the principal investigator of the study, described the “big threat” the cancer poses, underscoring that most patients diagnose quickly.
The standard treatment is maximum safe surgical resection, along with chemotherapy and radiation therapy designed to improve patient outcomes. Chen said he hopes, however, that this study will provide an opportunity for better targeted therapy based on the mutations and genetic drivers that his lab group identified.
The AAV was delivered to the mice through stereotactic surgery, which uses a three-dimensional coordinate system to precisely and consistently deliver the virus to a specific target area in the brain. Following AAV delivery, Guzman said, scientists could then use Cas9 to edit the genomes of the cells.
Guzman pointed out that consistent with data collected over recent decades, certain genes, such as common tumor suppressors PTEN and PI3K, were enriched in the study. The research also discovered epigenomic modifiers that were not previously appreciated as drivers of glioblastoma progression. Importantly, the paper concludes, “Several of the novel significantly mutated genes highly enriched in this mouse study have also been associated with glioblastoma multiforme in the clinical setting.”
By using this advanced model, patient treatment can become better tailored to certain mutation patterns. For example, the study showed that one mutation in a certain subtype of cells made them more resistant to temozolomide, an oral chemotherapy drug used to treat glioblastoma.
“We look at each mutation and determine what the response to the drug is,” Guzman said. “Certain mutations give more resistance than others.”
Using this information, he added, clinicians may prevent patients with resistant brain tumors from receiving toxic and unnecessary chemotherapy.
On the other hand, patients with mutations rendering cells sensitive to certain treatments may receive beneficial therapy. Ultimately, understanding the mutations that drive cancer will open up the doors for therapeutic intervention and targeted molecular therapy, according to Guzman.
Sen. John McCain, R-Ariz., was recently diagnosed with and underwent surgery for a primary glioblastoma at 80 years of age.
Contact Vikram Shaw at vikram.shaw@yale.edu .