Development and validation of a tumor-bearing model of oxaliplatin-induced neuropathy

Project Summary/Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment. The lack of successful pain therapeutic development for CIPN is ascribed in part to the use of relatively young, healthy, naïve animals. Given the emerging role of cancer-driven disruptions to the immune system in nervous system function, we propose to develop and validate a mouse model of CIPN with several key refinements which we hypothesize will result in a model with face, construct and predictive validity. Our preliminary studies indicate that colorectal cancer growth in mice is associated with subtle signs of polyneuropathy, including myelin dysregulation, loss of intraepidermal nerve fibers, systemic inflammation, hypercoagulability and deficits in fine motor coordination. Many of these pathological features have been reported in patients with colorectal cancer. This is crucial because one of the main factors in an individuals’ risk of developing CIPN is the presence of pre-existing neuropathy. We contend that this largely subclinical neuropathy driven by colorectal cancer is a major contributor to the subsequent pain and neuropathy experienced as a consequence of chemotherapy, and one that pre- existing models of CIPN do not capture. Therefore, the overall goal of this project is to develop and validate a mouse model of CIPN that replicates tumor growth, surgical resection and treatment with an adjuvant oxaliplatin-based chemotherapy regimen as closely as possible. The first aim will assess the impact of surgery and tumor growth on the subsequent development of sustained pain hypersensitivity in response to a FOLFOX-like (fluorouracil, leucovorin, oxaliplatin) regimen, establishing face and construct validity of the model. The second aim will determine the predictive validity of this model, comparing the efficacy of drugs that are recommended and not recommended for treatment of CIPN in the clinic. Our multidisciplinary approach involves a number of reflexive and non-reflexive tests of tactile and thermal sensitivity, along with assessments of motor coordination. Our project will unambiguously establish the impact of prior tumor growth on the development of painful CIPN in colorectal cancer. Establishing such preclinical CIPN models with predictive validity is critical to the development of new- generation, efficacious analgesics.