Scientists at the UNC Eshelman School of Pharmacy are using the newest version of a Nobel Prize–winning technology for the first time to build cancer-killing stem cells that hunt down and mop up the remnants of invasive brain tumors, promising a new and more effective treatment for glioblastoma, a cancer with very low survival rates.
“Glioblastoma patients desperately need something better, and we are trying to provide that with a better drug-delivery system,” said Shawn Hingtgen, Ph.D., an assistant professor in the School’s Division of Molecular Pharmaceutics and a member of UNC Lineberger who led the research effort.
With the standard treatment for glioblastoma, the median survival for a patient is less than a year and a half, and the chance of surviving beyond two years is 30 percent. Hingtgen and his team at the UNC Eshelman School of Pharmacy, School of Medicine and Lineberger Comprehensive Cancer Center are developing a new personalized treatment for glioblastoma that starts with a patient’s own skin cells. In mouse models, they increased time of survival 160 percent to 220 percent, depending on the type of tumor. Their work is described in an article published in Nature Communications.
Glioblastoma is difficult to treat. There are few options for traditional chemotherapy because the barrier that protects the brain from blood-borne pathogens also blocks many drugs. This makes surgery or radiation a frequent treatment choice. While surgeons can usually locate and remove solid tumors, it is nearly impossible to also cut out the invasive, cancerous tendrils that have spread deeper into the brain. And so the cancer almost always comes back.
Direct Reprogramming of Skin Cells
Hingtgen and his colleagues directly reprogrammed neural stem cells to seek and destroy the cancer left behind after surgery. The first step is to harvest fibroblasts — skin cells responsible for producing collagen and connective tissue — from the patient and then reprogram them to become what are called induced neural stem cells. Hingtgen’s team showed that these neural stem cells have an innate ability to home in on cancer cells in the brain and could also be given the ability to produce a cell-killing protein.
“Our work represents the newest evolution of the stem-cell technology that won the Nobel Prize in 2012,” he said. “We wanted to find out if these directly reprogrammed induced neural stem cells would home in on cancer cells and whether they could be used to deliver a therapeutic agent. They do, and they can. This is the first time this technology has been used to treat cancer.”
Hingtgen’s stem cells are inserted into the cavity created by the surgical removal of the tumor. From there, they then move out through the brain seeking and destroying any remaining cancerous cells. His team is currently improving this new drug-delivery system by focusing on human stem cells and testing a cancer-killing agent that is more appropriate for use in people.
Building a Scaffold
“We found that you can’t just drop a bunch of engineered stems cells into the brain by themselves and expect them to be an effective therapy,” he said. “They need some sort of physical matrix to support and organize them so they will hang around long enough to do the job. Without a structure like that, the stem cells disappear too quickly to do any good.”
By adding stem cells to an FDA-approved fibrin sealant commonly used as a surgical glue, Hingtgen made small patches that could be inserted in the cavity created when a tumor is removed. Fibrin is a fibrous protein involved in the clotting of blood, and the physical matrix it creates tripled the retention of cells in the surgical cavity when tested with stem cells from bone marrow. This technique is described in an article published in Biomaterials.
Hingtgen is collaborating with textile engineers at North Carolina State University to create a smart bandage infused with his cancer-seeking stem cells that can be left in the surgical cavity when the tumor is removed.
“Our goal is to get this therapy to physicians and patients as quickly as possible, so we wanted to see if we could successfully incorporate it into a product that is already FDA approved for use in people,” he said.
Co-authors and Funding
Hingtgen’s work is supported by the University Cancer Research Fund through UNC Lineberger and the North Carolina Translational and Clinical Sciences Institute.
In addition to Hingtgen, the authors of the Nature Communications article are
- Juli Bago´, Ph.D., postdoctoral research associate, UNC Eshelman School of Pharmacy;
- Adolfo Alfonso-Pecchio, Ph.D., UNC Eshelman School of Pharmacy;
- Onyi Okolie, graduate student, UNC Eshelman School of Pharmacy;
- Raluca Dumitru, M.D., Ph.D., director of the Human Pluripotent Stem Cell Core, UNC School of Medicine;
- Amanda Rinkenbaugh, graduate student, UNC School of Medicine;
- Albert S. Baldwin, Ph.D., Kenan Professor of Biology and Cancer Cell Biology and associate director of basic research at UNC Lineberger Comprehensive Cancer Center;
- Ryan Miller, M.D., Ph.D, associate professor, UNC School of Medicine, and a member of the UNC Lineberger Comprehensive Cancer Center; and
- Scott T. Magness, Ph.D., associate professor, UNC School of Medicine
In addition to Hingtgen, the authors of the Biomaterials article are
- Juli Bago´, Ph.D., postdoctoral research associate, UNC Eshelman School of Pharmacy;
- Guillaume Pegna, M.D., UNC School of Medicine; and
- Onyi Okolie, graduate student, UNC Eshelman School of Pharmacy.