The Department of Defense has awarded $1.15 million to a new research project at the University of Tennessee Health Science Center (UTHSC) that could expand the treatment options for breast cancer metastasis. Tiffany Seagroves, PhD, professor of Pathology in the College of Medicine, is the lead investigator. The project expands upon previously published research from her lab on the potential to treat breast cancer brain and bone metastasis by inhibiting creatine kinase pathway activity through the creatine kinase brain isoform protein (CKB).
Breast cancer is one of the most prevalent malignant tumors among women and the second major cause of female cancer-related mortality worldwide. Metastatic (stage IV) breast cancer is deadly. Up to 15-20% of breast cancer patients will develop metastasis to the brain, particularly women diagnosed with HER2+ or triple negative subtypes of breast cancer. Successful treatment of breast cancer brain metastasis is limited by the development of drug resistance prior to spread to the brain and by the need for treatments to cross the blood-brain barrier.
Most patients whose breast cancer has metastasized to the brain have also been diagnosed with metastatic lesions in 2-3 other sites (including bone, liver, or lungs). Bone is the most frequent site of metastasis in all breast cancers, regardless of the subtype.
Several key enzymes have been identified that modulate cancer metabolism, including creatine kinases, which are thought to fuel the energetic requirements of migrating cancer cells. CKB is expressed at high levels in the brain and in the bone; therefore, targeting this protein is a promising strategy to block the spread of breast cancer to multiple distant organs, including brain (the most difficult site to treat) and bone (the most commonly observed site).
The research project will test whether small inhibitors of creatine kinase activity known to cross the blood-brain barrier can prevent breast cancer metastatic spread or treat pre-existing metastatic disease. Drugs targeting the creatine kinase pathway will be tested alone, or in combination with currently FDA-approved systemic chemotherapies, such as doxorubicin or paclitaxel.
“These studies are based on our prior results that inhibition of creatine kinase activity primarily impacts cell invasion and mediates chemoresistance, two key components of metastatic disease,” Dr. Seagroves said. “Further, knowledge gained from these studies will likely directly impact other cancers that express high CKB protein levels, including brain, prostate, colorectal, lung, pancreatic, and ovarian cancers, providing new treatment options for a variety of aggressive solid tumor.” New generation creatine kinase pathway inhibitors similar to the ones Dr. Seagroves will be testing in pre-clinical animal models of aggressive breast cancer are already in clinical trials for GI and pancreatic cancers.