Back Row left to right: Michael Halvorsen, Jonathan Watts, PhD; Front row left to right: Traci Heath, Meg Halvorsen, Samantha Sarli, Jason Shohet, MD, PhD
When a family loses a loved one to cancer, they often seek ways to make an impact. After the Halvorsen family lost their 17-year-old son Patrick to glioblastoma multiforme (GBM) in 2021, they wanted to help others derailed by this disease. They started a fundraiser in Patrick’s name and donated the proceeds to UMass Chan Medical School to help researchers like fifth-year graduate student Samantha Sarli and her mentor Jonathan Watts, PhD, make headway on effective treatments for GBM and related cancers.
GBM is a deadly brain tumor with an ingenious defense system that helps it invade and conquer. The cancer snakes its way around normal brain tissue, obscuring the boundaries between healthy and diseased tissue, making complete tumor removal impossible. With tiny tumor remnants left behind to grow and flourish, recurrence is inevitable.
As stowaways in the brain, these culprits enjoy another line of protection—the blood-brain barrier—a network of blood vessels that shields the brain from harmful toxins. Although this security system is usually helpful, it lacks the sophistication to perfectly distinguish friend from foe, unwittingly barring entry to many beneficial drugs. And even when some therapies somehow breach the blood-brain barrier, GBM’s DNA repair mechanisms step in, rendering the drug ineffective.
Uber-prepared to overcome adversity, GBM prevails time after time—famous patients losing their lives to GBM include John McCain, Beau Biden and Ted Kennedy. Only 5% of GBM adult patients live more than five years and pediatric survival statistics are just as dismal.
The approach
To win the tug-of-war with GBM, we need to gain traction. Dr. Watts and his team are pursuing a line of inquiry that could provide a solution. Relying on their deep understanding of the chemical biology of nucleic acids, they weaponize oligonucleotides—short sequences of DNA or RNA consisting of bases held together by a sugar-phosphate backbone. These oligonucleotides can then bind to RNA with complementary code and silence the gene.
The team started by designing an oligonucleotide to silence a gene involved in GBM. The lab found that the drug worked well in healthy mouse brains, but when they implanted GBM tumors in mice, the drug did no better than the placebo in improving survival. Therefore, they surmised that the drug works differently in healthy vs. diseased cells.
Back to the drawing board
To make the drug effective in cancer cells, they needed to tweak the features. They didn’t change the oligonucleotide sequence because it matched that of the gene they were trying to silence and because Dr. Watts and others had already perfected the composition of the sugar-phosphate backbone, they left that structure alone as well. So, they decided to experiment with the chemistries of compounds they could attach to the drug to see if performance improved.
“We screened four or five [oligonucleotide] chemistries and tested them in tumor cells. We found that by attaching a fatty acid or other greasy molecule to the oligonucleotide, we were able to dramatically improve the drug’s activity in GBM cells in the brain,” Sarli says.
Next steps
The team understands that GBM is a master of metamorphosis, allowing drugs to work against it for only a limited time. Eventually, the tumor will learn to sidestep treatment by electing new genes to drive cancer growth and the team will be ready with newly tailored therapies to target them.
“For now, though,” Sarli says, “our focus is on developing the best chemistry for this first oligonucleotide to make it most effective.”
Sarli relishes her opportunity to watch an innovative idea evolve from a rudimentary concept into a promising treatment that may eventually help patients survive. For her, it just doesn’t get any better than that.
