Three Vanderbilt researchers have received a federal grant to study the use of nanoparticles to deliver potential therapies for breast cancer that has spread to the bone.
The grant from the Department of Defense Breast Cancer Research Program will provide more than $700,000 over three years in support of the research spearheaded by Julie Sterling, Ph.D., assistant professor of Medicine in the Division of Clinical Pharmacology, Cancer Biology, and Biomedical Engineering, Craig Duvall, Ph.D., assistant professor of Biomedical Engineering, and Scott Guelcher, Ph.D., associate professor of Chemical and Biomolecular Engineering and Biomedical Engineering.
Advances in treating primary breast cancer are more effective than ever at improving survival of breast cancer patients, according to Sterling, who holds a joint appointment at the Department of Veterans Affairs: Tennessee Valley Healthcare System. However, some patients still develop advanced disease which often spreads or metastasizes to bone.
“Sometimes it’s years after the primary cancer, when patients think they are essentially cured. Then they suffer a fracture and are told that they have a bone metastasis and that it’s terminal. At this point their options include local radiation for palliative care and bisphosphonate drugs which are also palliative.
“They help protect the bone but there is nothing right now available to kill the tumor,” said Sterling, whose research laboratory is based in the Vanderbilt Center for Bone Biology.
Tumors that develop inside bones are difficult to access with traditional drugs. Duvall has already developed nano-sized particles (1,000 times smaller than the width of a human hair) designed to deliver drugs to solid tumors based on the leaky blood supply of the tumor.
For this interdepartmental collaboration, the investigators hope to use the core structure of that nanoparticle and redesign it for use as a delivery system for drugs that target bones.
“We’re using a novel target called GLI2, a developmental protein which is overexpressed in tumor cells, including tumor cells in bone, but it is not found in most normal adult tissue,” Sterling said.
However, delivering a drug that targets GLI2 is tricky for several reasons. Instead of connecting to receptors found on the outside of the cell, the investigators are targeting a signaling pathway that operates within the confines of the cell. And many newly designed anti-cancer drugs are insoluble.
That’s where Duvall’s nanoparticle comes into play.
“Nanoparticles allow us to deliver a water-solubilized embodiment of the drug intravenously that will preferentially accumulate at bone tumor sites where the drug will be released over time in response to cues within the tumor microenvironment,” said Duvall, who also serves as director of Graduate Recruiting in Biomedical Engineering.
Guelcher and his team of engineers are also deeply involved in the design and construction of the nanoparticles.
“New therapies designed to slow the progression of disease in bone must not adversely affect bone healing. Drugs targeting GLI2 are not expected to slow bone healing, since this protein is specific to the tumor cells,” Guelcher said.
The investigators have already successfully tested some promising therapies in cancer cell lines and will now test those therapies in a mouse model.
Sterling said the investigators eventually hope to find a way to prevent tumors from establishing in bone or to slow the growth of the bone tumors, which are extremely painful for patients.
“Even if this doesn’t cure the patient, we are trying to develop and deliver therapies that have a significant chance of giving patients more quality time,” Sterling said.
