Detection and Treatment of Ovarian Cancer by Targeting Tumor Extracellular Hydroxyapatite: A New Paradigm
Abstract
Ovarian cancer is a deadly disease. Most women are first diagnosed at a late stage of disease, when the cancer has already spread through the abdominal cavity. Tragically, less than half of all patients are still alive 5 years after diagnosis. There are key decisions that a patient’s oncologist must make in order to treat her most effectively. Finding new ways to increase the information available to an oncologist to guide these decisions is a critical priority to increase quality of life and survival times for patients. The first decision that an oncologist has to make is whether a patient should first undergo surgery to remove the cancer, then be treated with drugs to kill the tumor (“chemotherapy”) or vice versa. Surgical planning is currently based on analysis of two different kinds of medical imaging, computed tomography (CT) and positron emission tomography (PET), using a form of radioactively labeled glucose to detect cancer cells that have high metabolic activity (18F-FDG). However, distinguishing between tumor and normal tissue is not trivial with these conventional methods. Therefore, unfortunately for ovarian cancer patients, these imaging tools often fail to fully detect the extent and location of the cancer, making this initial decision more difficult. Better methods of detecting ovarian tumors are urgently required. Even in patients who do respond well after surgical removal of their tumors and drug treatment, tumors frequently come back and respond less well to a second round of chemotherapy. Another key decision by the oncologist is whether to treat patients with the same chemotherapy drugs or use a different kind of treatment. Unfortunately, treatment choices for tumors that come back are often a matter of trial and error. There are limited ways to predict response to treatment and make an early assessment whether the treatment is working. All of these factors may lead to patients being treated with ineffective and toxic therapies. New treatment strategies are also urgently required. We will use a new strategy that addresses key issues identified above that limit the effectiveness of ovarian cancer treatment. Our idea is to use a feature of ovarian cancer that we have newly discovered to improve imaging/detection and treatment of tumors. Normally a constituent of bone, calcium-containing hydroxyapatite (HAP) is also made by ovarian cancers and deposited outside the tumor cells in what is known as the “extracellular matrix.” We provide evidence for the first time that extracellular HAP in ovarian tumors in mice can be imaged by radioactively labeled sodium fluoride (18F-NaF) by PET imaging. Importantly, HAP is absent in normal soft tissue in the abdominal cavity and so only HAP-containing tumors are detected. Tumor extracellular HAP imaging is comparable or better at detecting ovarian tumors than the established imaging techniques (CT and 18F-FDG PET). We have also analyzed the presence of HAP in tumor tissue from ovarian cancer patients. Preliminary analysis shows that patients with tumors that contain extracellular HAP are more likely to respond to chemotherapy than patients whose tumors lack extracellular HAP. In this application, we aim to show that tumor extracellular HAP in ovarian cancer is a unique and highly attractive target for assessing tumor extent and location; patient selection for chemotherapy versus surgical removal of the tumor, a marker of disease response to therapy; and is a target itself for therapy. We have also developed a new cancer treatment drug, a nanoparticulate sulfonated polystyrene solution (NSPS) to dissolve tumor extracellular HAP. The ions left in the extracellular matrix of the tumors have been found to rapidly kill breast tumors (within 24 hours of application) and are expected to have the same impact on ovarian tumors. Furthermore, since HAP is absent in soft tissue, treatment with NSPS had no apparent side effects on mice. We will test N
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010269
Entities
People
- Mohammed Tantawy
Organizations
- United States Army
- Vanderbilt University