Illuminating NETs
The neuroendocrine system, which bridges the nervous system with the endocrine (hormonal) system, touches almost every cell in the human body. It is responsible for creating quick and effective reactions to environmental stimuli, like activating your “fight or flight” response.
Because the neuroendocrine system is so well distributed in the body, cancers that affect it-known as neuroendocrine tumors (NETs)-can be extremely difficult to locate. NETs can also hijack the hormonal machinery, leading to a wide variety of symptoms.
“Not all cancers are the same, so people may present with different symptoms in each case,” said Alexis Sanwick, a PhD student in the Department of Nuclear Engineering (NE). “But those tumors also have specific characteristics we can leverage.”
Sanwick researches radiopharmacology, the use of drugs with radioactive atoms to diagnose and treat diseases like cancer, in the laboratory of NE Assistant Professor Ivis Chaple Gore. Unlike external radiation and chemotherapy, radiopharmaceuticals are designed to deliver imaging or therapeutic compounds straight to the tumor—and stay there.
For several years, Sanwick and others in the Chaple Lab have been developing a new radiopharmaceutical that they hope will improve patient outcomes by giving doctors a more accurate estimate of dosimetry, or how much ionizing radiation will be delivered to a NET.
Their work was published in the European Journal of Nuclear Medicine and Molecular Imaging (EJNMMI) Radiopharmacy and Chemistry last December. It was Sanwick’s first time leading—or even contributing to—a research paper.
“We are very proud that EJNMMI found our work important enough to publish and are hopeful that this will lead to new collaborations across the globe,” Chaple Gore said.
Improving Dosimetry Estimates
Radiopharmaceuticals are made of a radioactive metal (radiometal) atom attached to a molecule that binds to the targeted cancer cells. Depending on the atom, the radiopharmaceutical may be for imaging or treatment.
In 2018, the United States Food and Drug Administration approved the first radiopharmaceutical for NET treatment, Lutathera, which kills tumors with radiation from lutetium-177 (Lu-177) atoms.
To determine whether a patient’s NET will respond to this treatment, the patient is injected with an imaging radiopharmaceutical that uses the same cell-binding component as Lutathera. If the imaging drug appears in one area on a positron emission tomography (PET) scan, doctors can both find the tumor and confirm that Lutathera will accurately target it.
Unfortunately, while Lu-177 has a half-life of six days, current NET imaging radiopharmaceuticals use isotopes with half-lives on the order of hours or even minutes.
“Predicting the dose of Lutathera using a shorter-lived radiometal may lead to dose estimation errors,” Sanwick said. “We want to develop a PET agent that can more accurately predict the dose from the therapeutic agent.”
Sanwick determined that zirconium-89 (Zr-89) could be a great candidate radiometal for imaging. The isotope is a positron emitter, so PET scans will detect it; its chemical characteristics play well with a commercially available NET-binding molecule called octreotide; and with a half-life just over three days, it should be a better pair for Lutathera than the standard options.
Tests of the drug in mouse serum were a major success. The new radiopharmaceutical bound specifically to NET cells and was stable enough to allow imaging across several days, a potentially groundbreaking result for the study of Lutathera dosimetry.
Better Predictive Dosimetry
Chaple Gore mentors Sanwick and her fellow graduate students in radiochemistry, cell cultivation and animal studies, then allows them to work independently once they are trained.
“I am very supportive of sound scientific freedom for graduate students,” Chaple Gore explained. “I am always excited when they come to me with new experiments they want to try; it means that they are developing into budding young scientists and are preparing for their independent careers.”
For her part, Sanwick is not discouraged by setbacks or the need to tweak her experimental design. When challenges arise, she focuses on her long-term goal: improving survival rates for NET patients.
“The best-case scenario would be that our system is a better alternative for Lutathera predictive dosimetry,” she said. “If not, we still developed a novel radiopharmaceutical, and we’ll keep building on it.”
Contact
Izzie Gall (865-974-7203, egall4@utk.edu)