MnBuOE as a Novel Chemosensitizer for Breast Cancer and Neuroprotector

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Project Summary Background: The cognitive deficits observed after treatment with chemotherapeutic drugs are a significant clinical problem, with a rapidly increasing impact on the quality of life of millions of Americans. One and a half million people are diagnosed with cancer every year in the US, and more than 60% survive for 20 years or more. Cancer survivors have long reported cognitive dysfunction at various stages of the disease course with associated consequences upon well-being and functional independence. Several studies conducted over the past decade have indicated that cognitive impairment occurs long before cancer treatment begins and even before cancer diagnosis. Despite collective evidence for cognitive problems, far less is known about how tumor biology and cancer treatments can interact to lead to changes in the brain. The present study will use an orthotopic mouse model of breast cancer to delineate the effects chemotherapy on cognitive function. Moreover, we will test whether a novel antioxidant is capable of preventing the development of chemo/tumor- induced cognitive dysfunction. Hypothesis: We hypothesize that oxidative stress induced by chemotherapy treatment leads to changes in neuronal architecture and mitochondrial function impairing cognition which will be rescued by MnBuOE. Furthermore, Nrf2 function is critical for supporting neuronal maintenance after chemotherapy when aberrant ROS production is known to be exacerbated. Specific Aim 1: Determine if pharmacological upregulation of Nrf2 by MnBuOE protects the brain from chemotherapy induced injury. Aim 1.1) We will use a knockout model to determine if Nrf2 contributes to the protective effect of MnBuOE toward AC-T-induced brain injury. Aim 1.2) Determine if impaired Nrf2 expression plays a critical role in the pathogenesis of chemotherapy- induced brain injury. Specific Aim 2: Characterize the behavioral, neuroanatomical and morphological changes due to chemotherapy and the remediating effects of MnBuOE in a syngeneic model. Aim 2.1) Characterize mitochondrial bioenergetic changes in the brain associated with tumor ± chemotherapy and the effects of MnBuOE treatment. Specific Aim 3: Assess the influence of MnBuOE on tumor growth and susceptibility to chemotherapy (AC-T) in a patient derived tumor bearing animal model