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Naomi Lomeli, PhD Neurology Mentor: Dr. Daniela Bota, MD, PhD |
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Project Title: Novel Translational Mechanisms for the Prevention of Cancer-Related Cognitive and Neuropathic Impairments |
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I am a post-doctoral fellow in the Department of Neurology under the mentorship of Dr. Daniela A. Bota. My primary research interest is the development of novel therapies for the treatment of neurological impairments associated with cancer and cancer treatment. This proposal focuses on an understudied problem faced by cancer survivors – the adverse neurotoxic sequelae associated with cancer treatment. Chemotherapy-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) are debilitating side-effects of cancer treatment with platinum agents (e.g., cisplatin), taxanes, and vinca alkaloids. CRCI encompasses impairments in memory, attention, executive functioning, and information processing speed. CIPN symptoms include painful paresthesia, numbness, motor weakness, gait changes, increased disability, and tendency to fall, limiting patient mobility, and impairing quality of life. Cisplatin is widely used as a chemotherapeutic agent to treat ovarian malignancies. Over 30-70% of survivors experience CRCI/CIPN years after completing chemotherapy, impairing their quality of life. Currently, there are no FDA-approved clinical interventions for the treatment of CRCI and CIPN. Mechanistically, cisplatin-induced neuronal toxicity derives from nuclear and mitochondrial DNA damage, and oxidative stress, which induce the activation of the p38 mitogen-activated protein kinase (p38MAPK) leading to neuronal apoptosis. Exciting preliminary data show that in vitro pharmacological inhibition of p38MAPK prevents cisplatin-induced reduction in neuronal dendritic spine branching and density. The aims of this project are to determine if: (1) cisplatin-induced p38 MAPK signaling underlies structural and functional neuronal damage, using in vitro pharmacological inhibition and siRNA silencing; and (2) p38MAPK pharmacological inhibition prevents cisplatin-induced neuropathy and gait alterations in an ovarian cancer mouse model. These studies will provide evidence that the p38MAPK pathway is involved in cisplatin-induced CRCI/CIPN and is a druggable target. Investigating the contributions of chemotherapy and cancer in the development of CRCI/CIPN in a female cancer mouse model will advance understanding of the quality of life of women with cancer and/or affected by cisplatin-related complications. The findings may lead to translationally relevant functional outcomes: improved cognitive function and reduced pain associated with cisplatin, which will provide supporting evidence for translational potential and future testing in clinical trials. |
