This proposal seeks to examine mechanisms of paclitaxel-induced peripheral neuropathy by emphasizing on epidermal damage and the role of the matrix-degrading enzyme Matrix-metalloproteinase 13 (MMP-13) in this process. Paclitaxel is a chemotherapeutic agent that is used in the treatment of common cancers, such as lung, breast, and ovarian cancer. Paclitaxel functions by arresting tumor cell division through stabilization of the microtubule cytoskeleton, which induces cell death. The non-selective nature of paclitaxel?s action also causes damage to healthy cells, leading to side effects such as peripheral axon degeneration (neuropathy). Paclitaxel- induced peripheral neuropathy affects about 70% of patients undergoing chemotherapy. Patients present with symptoms, such as numbness, tingling, temperature sensitivity and pain. These symptoms differ in their severity but patients that suffer most severely must either reduce the dose or terminate chemotherapy, which deprives them of the full benefits of cancer treatment and decreases their life expectancy. The lack of understanding about the underlying mechanisms has prevented the design of effective treatments. Because microtubules are abundant in axons, it is generally accepted that neuron-intrinsic defects, such as microtubule aggregation, aberrant microtubule transport, and mitochondrial damage that stimulates oxidative stress promote axon degeneration. Whether these defects are a cause or consequence of axon degeneration is unclear. To address this question, my lab established a zebrafish in vivo model that permits studying the dynamics of paclitaxel-induced axon degeneration in the living animal. These studies showed that paclitaxel treatment increases the activity of the matrix-metalloproteinase 13 (MMP-13) in the epidermis, leading to epidermal damage and axon degeneration. The proposed project analyzes the mechanisms underlying MMP-13 expression and function, as this understanding will be critical for pre-clinical and clinical studies assessing MMP-13 as a clinical target in the treatment of paclitaxel-induced peripheral neuropathy.
Specific aim 1 will investigate the role of stabilized microtubules and mitochondrial damage in oxidative stress formation and MMP-13 expression.
Specific aim 2 will assess the functions of MMP-13 in axon degeneration. In addition, in collaboration with Mayo Clinic we will analyze skin biopsies of paclitaxel-treated mild breast cancer patients to examine MMP-13 expression changes and the potential of epidermal damage. Preliminary data shows that paclitaxel treatment induces MMP-13 expression in a human keratinocyte cell line, indicating that the mechanisms are conserved. The findings in this project may have broader applicability also for other neuropathies in which oxidative stress is a hallmark, including those that are induced by different chemotherapeutic agents, fluoroquinolone antibiotics and diabetes.
This research seeks to explore mechanisms of paclitaxel-induced peripheral neuropathy, a condition of nerve damage by focusing on the dysegulation of matrix-metalloproteinase 13 in the epidermis as underlying cause of nerve degeneration. This project will lay the groundwork for future therapeutic studies in which two identified MMP-13 targeting compounds with high efficacy in preventing nerve degeneration will be further tested for clinical applications.
|Waldron, Ashley L; Schroder, Patricia A; Bourgon, Kelly L et al. (2018) Oxidative stress-dependent MMP-13 activity underlies glucose neurotoxicity. J Diabetes Complications 32:249-257|