by Mark Wheeler
Like an arrow shot at a target, neural stem cells (NSCs) home in on primary invasive tumors in the brain. Now, Karen Aboody, M.D., assistant professor, Division of Hematology & Hematopoietic Transplantation, City of Hope Cancer Center, has taken advantage of this natural ability of NSCs, using them as transport vehicles to attack multiple tumor sites in a preclinical model of melanoma metastases to the brain. The approach resulted in a 70 percent reduction in the tumor burden or volume following treatment. Researchers believe NSCs hold great promise for the development of therapies to primary and metastatic brain tumors.
The research by Aboody and collaborators at Tufts-New England Medical Center and Brigham and Women’s Hospital, Boston, Mass., appeared in the April 6 issue of the journal Neuro-Oncology.
Many types of cancer, including melanoma, breast and lung, metastasize to the brain. Metastases are the most common form of brain tumor; each year, more than 100,000 people in the nation are diagnosed with brain metastases. Currently, there are no highly effective treatments – radiation has many negative side effects, surgery is generally not an option for multiple brain tumors, and many chemotherapeutic drugs do not cross the blood-brain barrier.
In work conducted at Harvard University in the 1990s, Aboody and her colleagues were the first to discover that NSCs naturally migrate to brain tumors and track cancer cells that have invaded surrounding tissue away from the main tumor site. She also showed that NSCs could be used as delivery vehicles to selectively distribute therapeutic gene products to gliomas, the most aggressive type of primary brain tumor.
“Although there are several theories, no one really understands why neural stem or progenitor cells target tumor sites; it’s one of the focuses of our current investigations,” said Aboody. “Presumably, signals of some kind are being sent out by the tumor that attracts them, even from a distance.”
The current study moves the research another step forward toward clinical trials. First, Aboody and her collaborators genetically engineered neural stem/progenitor cells, or NSPCs (progenitor cells are partially specialized stem cells) to carry an enzyme called cytosine deaminase (CD). Once the administered NSPCs reached the multiple sites of melanoma brain metastases in the rodent model, the CD was expressed (or turned on) to convert a nontoxic drug, 5-fluorocytosine (5-FC), into an active chemotherapeutic drug, 5-fluorouracil (5-FU), in effect localizing the chemotherapy to the tumor sites.
Unlike many other drugs, the benign 5-FC can cross the blood-brain barrier. Once it reaches the CD-secreting NSPCs at the tumor sites, only then is it converted to the active drug 5-FU. “Since the CD enzyme is only expressed by the NSPCs at the tumor sites, you effectively get localized production of the 5-FU chemotherapeutic,” said Aboody. “The drug selectively attacks the surrounding tumor cells that are dividing, minimizing the toxicity to normal brain tissue, and minimizing toxicity to normal cells in the body that divide rapidly, like skin and intestinal cells.”
Although the work serves as a “proof-of-concept” that NSPCs can carry a gene product directly to multiple brain tumor sites and dramatically reduce their size, more research is needed to determine the correlation between tumor reduction and increased survival. Preclinical studies are now under way at City of Hope to identify treatment doses and schedules that will maximize therapeutic efficacy and long-term survival.