Dual PET/Fluorescence Imaging of Glioma with an MMP-14-Activatable Peptide Probe
Abstract
Glioblastoma multiforme (GBM) is the most common type of brain cancer in adults. There is no cure for GBM, and the majority of patients die less than 14 months after the tumor is detected. Treatment options include surgery to remove as much of the cancer cells as is safe for the patient, as well as radiation and chemotherapy. Studies have shown that using surgery helps to prolong survival, although surgeons have difficulty distinguishing the cancer cells from normal brain tissue. Because of this challenge, cancer cells that spread outside of the main tumor area are not removed during surgery, and many of these cells are resistant to radiation and chemotherapy. These surviving cancer cells cause GBM to recur and result in patient death. The proposed studies will use a new strategy for doctors to specifically detect GBM cells throughout the brain. Knowing where the GBM cells are located and how many are present can help doctors plan the best treatment for patients with GBM. GBM cells make a type of protein called MMP-14 that is not made by normal brain cells. This project will develop a molecule that can detect MMP-14 with high sensitivity through two different techniques to help doctors identify as many GBM cells as possible. The molecule will contain a radioactive element that is commonly used in medicine so doctors can detect the location of the GBM cells before surgery. The molecule will also contain a fluorescent dye that can be detected with a special light during surgery. The dye will not be visible with the light until the dye is activated by MMP-14 on the GBM cells; normal brain cells will not activate the dye. Surgeons can then distinguish GBM cells that activate the dye from normal cells. Therefore, this strategy will help doctors remove as many GBM cells as possible during surgery, thus reducing the likelihood of recurrent GBM growth. During this project, the new molecule will be injected into mice that have GBM tumors growing in their brains. The mice will be used for imaging with the radioactive element and with the fluorescent dye. The studies will determine where the molecule goes throughout the body of the mice and will determine how many GBM cells the molecule can specifically detect. These studies are important first steps to optimize the structure of the molecule for detecting small numbers of GBM cells with high specificity. Next stages of research will use optimized versions of the molecule in surgery experiments to remove GBM cells from brains of mice, and later from other animals that spontaneously develop brain tumors. These studies will provide information that can eventually help doctors more accurately determine different types of brain cancer and what treatments will be most effective against the cancer. After completing these studies, additional safety studies in animals will need to be performed to ensure the molecule does not have toxic side effects. Toxic effects are not expected because a very small amount of the molecule will be used during imaging. Once the studies in animals are finished, the new molecule could be studied in patients with GBM within the next 5-7 years. The proposed imaging strategy would be likely to benefit patients immediately after they are diagnosed with brain tumors. This strategy is particularly relevant for military personnel because exposure to radiation, including nuclear weapons testing, is the main risk factor associated with GBM. Studies have also shown that officers in the Air Force also have increased risk compared to Servicemen for developing brain tumors. Besides the burden of increased risk of brain tumor development due to military occupation, military personnel who have relatives with brain tumors are understandably concerned for their loved ones. The poor prognosis of this disease could negatively impact the psychological well-being of Service personnel and potentially jeopardize their active-duty performance. The new ima
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810160
Entities
People
- Jason M Warram
Organizations
- United States Army
- University of Alabama at Birmingham