Glioblastoma multiforme is the Miley Cyrus of cancers: once it gets into your brain, it is completely incurable, and leads to the untimely death of those unlucky enough to be afflicted in only 14 to 16 months. In short, it comes in like a wrecking ball.
But it isn’t infuriatingly catchy hooks that keeps the most deadly of cancers inside your noggin; it’s the complete inability to treat the disease. Cancers on their own in any part of the body are a complete bitch to treat. Add to that the delicate nature of the neurons that makes you you and the nearly impenetrable wall of twerking tweens that is the blood-brain barrier, and you have the inevitable death sentence that no doctor wants to have to give.
Like many cancers, glioblastoma causes problems at least in part by shutting off a cell’s natural end-of-life-cycle apoptosis – programmed cell destruction because of either age or genetic malfunction. Not only does this cause the buildup of damaging cells that creates a tumor, but it makes said tumor resistant to most forms of cancer-fighting medications.
Naturally, there are many research teams across the world trying to at least create a better prognosis for glioblastoma, if not figure out a way to cure it. And thanks to a recent study from Northwestern University, one research team may finally be making some headway.
The key to the emerging therapy is spherical nucleic acid nanoparticle conjugates. That is, tiny gold nanoparticles surrounded like a ball of rubber bands with genetic material. The resulting spheres are tiny enough not only to cross the blood-brain barrier, but also to wiggle their way into cells. Normal, linear lines of nucleic acids can’t.
So what do these tiny balls of genetic sequences do?
If you want to silence the actions of a gene, there are several ways to go about it. You can try to block the DNA that is the basis of all of life’s biomolecular instructions. Or you can try to interfere with the RNA that is sort of like the body’s foremen – it reads the blueprints (DNA) and instructs the workers (ribosomes) how to build proteins. The new therapeutics take the latter route.
Once inside the cell, the nanoparticles latch on to very specific strands of RNA after they have read the blueprints but before they can get to the construction sites. And as you might have guessed, the RNA that they end up blocking are trying to deliver faulty instructions.
One of the many cancer-causing mutations that scientists have managed to find is called Bcl2L12. In glioblastoma tumors, this gene is way overactive (like Miley with teddy bears and Robyn Thicke). This is a problem because Bcl2L12 silences a protein called p53, which has been called “the guardian of the genome” because it kills off cells with mutations to its DNA.
So in short, the tiny balls of genetic material latch on to the RNA containing its counterpart genetic match, effectively silencing the overactive gene that is stopping a cellular janitor from doing its job. This causes the cancer to become more susceptible to other forms of cancer treatments.
The researchers tested their new therapeutic in mice that had human glioblastomas surgically grafted into their brains. Although the new treatment did not prove to be a silver bullet, it did help the mice live longer. The survival rate was bumped up by nearly 20 percent and tumor size was reduced three to four fold, as compared to the control group.
“This is a beautiful marriage of a new technology with the genes of a terrible disease,” said Chad A. Mirkin, a nanomedicine expert and a senior co-author of the study. “Using highly adaptable spherical nucleic acids, we specifically targeted a gene associated with [glioblastoma multiforme] and turned it off [in a living animal]. This proof-of-concept further establishes a broad platform for treating a wide range of diseases, from lung and colon cancers to rheumatoid arthritis and psoriasis.”
“My research group is working to uncover the secrets of cancer and, more importantly, how to stop it,” said Alexander H. Stegh, a senior co-author of the study. “Glioblastoma is a very challenging cancer, and most chemo-therapeutic drugs fail in the clinic. The beauty of the gene we silenced in this study is that it plays many different roles in therapy resistance. Taking the gene out of the picture should allow conventional therapies to be more effective.”
The study, “Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma,” was published in the journal Science by Mirkin, and Stegh. The co-first authors are Samuel A. Jensen, Emily S. Day and Caroline H. Ko. In addition to these three, Mirkin and Stegh, other authors of the paper are Lisa A. Hurley, Janina P. Luciano, Fotini M. Kouri, Timothy J. Merkel, Andrea J. Luthi, Pinal C. Patel, Joshua I. Cutler, Weston L. Daniel, Alexander W. Scott, Matthew W. Rotz, Thomas J. Meade and David A. Giljohann, all from Northwestern.