Protection Against Chemotherapy Adverse Events by Macromolecular Superoxide Dismutase Mimetics in Breast Cancer
Abstract
Metastatic cancer is particularly a concern with triple-negative breast cancer (TNBC) for which standard cancer treatments may not be effective. Brain health is adversely affected by cancer in at least two ways: 1) direct invasion of the brain by cancer either from primary brain cancer and from metastatic spread for cancer elsewhere in the body and 2) cognitive impairment associated with cancer treatments, especially chemotherapy, commonly known as chemobrain. This complication of chemotherapy occurs in 10%-40% of cancer patients and is a particular problem in breast cancer patients. While it may be transient, in some individuals cognitive impairment and memory problems persist long after chemotherapy is completed. Chemotherapy-induced oxidative stress has been linked to this cancer-related cognitive impairment, but there are currently no therapies available to treat this serious cancer complication. The proposed research addresses both of these concerns with use of a substance, polynitroxylated albumin (PNA), which has been shown to protect the brain from other insults, such as strokes, without significant side effects. PNA functions similarly to superoxide dismutase (SOD) and catalase, which are naturally occurring enzymes, which function to break down biologically damaging reactive oxygen species (ROS). We have previously shown that PNA decreases cancer cell proliferation, significantly reduces metastases, and increases survival when used in conjunction with standard chemotherapy in a highly metastatic mice model of TNBC. PNA also prevents chemotherapy damage to key areas of the brain that are associated with chemobrain. These beneficial neuroprotective effects are associated with reduced cellular ROS and increased tumor blood flow. In addition to PNA, we will include another SOD mimetic, SanFlow, which is also an effective catalase mimetic and may have more anti-cancer activity than PNA. PNA and SanFlow are both SOD-mimetics but do differ in that PNA distributes to the extravascular spaces, whereas SanFlow has an intravascular distribution. Our research methodology builds on our previous experience using of PNA in a mouse model for TNBC. In the proposed study, we will assess the effects of PNA and SanFlow on 1) chemotherapy-induced brain oxidative stress, in addition to their effects on tumor growth and brain metastasis; 2) chemotherapy-induced chromatin modifications in brain neural tissue; 3) chemotherapy-induced changes in neural growth and differentiation; and 4) chemotherapy-induced effects on behavioral and cognitive impairments. Experiments will be conducted first with PNA, followed by similar studies with SanFlow. Our research team is experienced with the murine model for TNBC and also has expertise in the outcome measures we will use, including measuring tumor growth, metastasis, and examination of brain for neurological damage. Dr. Hsia has extensive experience with both PNA and SanFlow and has shown both drugs to be neuroprotective in models, of stroke, traumatic brain injury, and hemorrhagic shock. In summary, the proposed research will determine whether treatment with SOD mimetics, which can be safely administered to humans, protects against neurologic damage and cognitive impairment in the highly relevant breast cancer animal model. This information is critical to future development of cancer therapeutics that minimize toxicity and improve the quality of life for cancer survivors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110023
Entities
People
- W. Miskimins
Organizations
- United States Army