Any potential cure for glioblastoma multiforme (GBM) — the most common and aggressive form of brain cancer — must first overcome one of nature’s most formidable obstacles.
The blood-brain barrier, which keeps potentially diseased blood from reaching the brain, is nearly impenetrable. So when Alexander Stegh, neurology and medicine, saw his lab’s preliminary 2013 results on breaching the barrier, he was understandably intrigued.
The lab had tracked an injection of spherical nucleic acids (SNAs) from a rodent’s tail vein to the site of a brain tumor — a systemic approach to drug delivery that could prove revolutionary.
“The development of a therapeutic vehicle that can stably and robustly deliver small molecules to a brain tumor was groundbreaking,” says Stegh, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the International Institute for Nanotechnology (IIN), one of Northwestern’s more than 50 interdisciplinary research hubs. “Those early findings illustrated that our technique had the potential to be used as a systemic therapy.”
No Barriers to Collaboration
Stegh arrived at Northwestern in 2009 already knowing which cancer gene he wanted to target. Two years earlier, a team he led at the Dana-Farber Cancer Institute discovered that the BCL2L12 gene is overexpressed in glioblastoma and is likely related to the tumor’s resistance to conventional therapies. The hope was that, by knocking out the gene, researchers could weaken the cancer’s ability to thrive.
But Stegh still needed to find a way past the blood-brain barrier.
By design, one of his first meetings at Northwestern was with IIN Director Chad Mirkin, the George B. Rathmann Professor of Chemistry and a member of the Lurie Cancer Center. Mirkin had the perfect vehicle: SNAs, which he invented at the University in 1996. The first-generation SNAs consist of a gold nanoparticle surrounded by a corona of short DNA or RNA molecules. The nucleic acids are densely packed to form a tiny sphere, which allows them to enter the brain.
“Glioblastoma provided a great opportunity to test the potential of the SNA platform,” says Mirkin, a world-renowned nanoscientist who has received more than 100 national and international awards for his work. “Getting drugs across the blood-brain barrier is not trivial. We originally thought we would have to postoperatively deliver the SNAs in a topical manner, but we quickly discovered that they could be systemically administered, with enough of them entering the brain to be considered effective.”
Stegh and Mirkin coauthored the publication of this 2013 research breakthrough, which concluded that gene regulation technology could reduce glioblastoma progression and increase survival rates in mice with GBM. The SNA nanostructures for the protocol were developed in Mirkin’s lab in Evanston, while the animal studies were conducted in Stegh’s lab in Chicago.
“As far as our collaboration goes, the two campuses work as one; it’s seamless,” says Stegh. “One of the reasons I wanted to come to Northwestern was the University’s reputation in nanotechnology and nanomedicine.”
It is highly unusual for a university, after developing a drug in preclinical research, to also secure Food and Drug Administration approval of a clinical trial and conduct the trial. But that is exactly what Stegh and Mirkin have accomplished.
Involving about 10 patients, the ongoing Phase 0 trial at the Lurie Cancer Center is designed to investigate the drug’s ability to reach brain tumors in humans. Cancer Center member Priya Kumthekar, neurology and hematology–oncology, is clinical director of the project, expected to conclude in early 2018.
“Progress like this is the result of collaboration across disciplines,” says Lurie Cancer Center Director Leonidas Platanias. “By providing our exceptional physicians and scientists with access to state-of-the-art technologies and infrastructure, we’re able to take innovative research to the next level. When we take on cancer as a team, breakthroughs happen.”
The drug, currently known as NU-0129, consists of RNA snippets arranged on the surface of spherical gold nanoparticles. When the drug reaches the tumor, it alters the genetic makeup of cancer cells to slow their division.
There is no cure for GBM, though patients are often treated with chemotherapy, radiation, and surgery. In July, Senator John McCain (R-Ariz.) became one of the more than 20,000 people in the United States diagnosed annually with GBM. According to the American Association of Neurological Surgeons, the average life expectancy after diagnosis is just 15 months.
New Class of Drugs
While the early-phase trial is continuing, Stegh and Mirkin continue to explore other avenues for the SNA platform.
“We are actively working on using SNAs for the treatment of other cancers and other diseases of the central nervous system,” says Stegh. “One of our goals is to leverage the enormous capacity of these SNA particles to accumulate in tumors and apply the technique for the treatment of other cancers, like metastatic melanoma.”
When imaging melanoma metastasis, researchers and physicians typically see the formation of cancer in many different areas of the body, says Stegh. Preliminary investigations in animal models have shown that, when specially designed SNAs are injected systemically, they localize to the different metastatic sites.
“Because of our success with GBM, there’s also a logical expansion into potential treatments of other neurological diseases such as Alzheimer’s and Parkinson’s disease,” says Stegh. “Being able to deliver a drug across the blood-brain barrier is a critical aspect in the therapeutic success, so in that regard, SNAs could be a game changer.”
Although chemotherapy remains one of the most popular ways to treat cancer, it’s a broad approach that takes advantage of how rapidly cancer cells grow in comparison with normal cells. Because cancer cells divide more often, chemotherapy is much more likely to kill them. However, the treatment also damages active healthy cells, like those in blood and hair follicles.
“The SNA model represents a precision medicine approach,” says Stegh. “For instance, if we can very precisely identify the genetic underpinnings of GBM, we can define which genes drive or contribute to the disease and then try to develop therapies that specifically target them.”
By designing small RNA molecules to specifically turn off the expression of certain genes that are associated with cancer progression and are not essential for noncancerous tissue, the research team hopes to spare more normal cells.
“We’re certainly not done trying to enhance the antitumor efficacy of SNAs,” says Stegh. “As we think of different strategies to enhance tumor-specific uptake, we bring them to the Mirkin group, and researchers there develop new chemistry for us to test.”
Stegh says that process is not necessarily typical in nanomedicine, a field where most researchers develop a construct and deploy it without fully optimizing it.
“We wanted to approach this from a different angle, from more of a small-molecule, conventional pharmacological viewpoint,” explains Stegh. “The idea being that these structures have different components, and we can ask very rational questions about how changes in SNA chemistry affect tumor uptake and gene knockdown.”
For instance, what happens if the core material is made smaller, or larger, or its shape is changed? If the density of RNA molecules is altered or different peptide chemistries are added to increase tumor-specific uptake, does that enhance the SNA’s antitumor effect?
“There are a lot of different parameters we can test,” he says, “and we will work to do so over the next couple of years.”
In seeking to optimize the chemistry, the researchers are using part of a five-year, $11.7 million grant from the National Cancer Institute to Northwestern’s Center of Cancer Nanotechnology Excellence — an NCI-funded collaboration between the Lurie Cancer Center and IIN.
Editor’s note: Northwestern University, Alexander Stegh, and Chad Mirkin have financial interests in the drug used in the Phase 0 research study. As a result of these interests, each could ultimately benefit financially from the outcomes of the research.