PROJECT SUMMARY Oxaliplatin (OX) is effective as the primary treatment for metastasized colorectal cancer and an adjuvant treatment for other gastrointestinal neoplasms. Despite its efficacy, OX can lead to neurotoxicity, resulting in physical dysfunctions including a loss of dexterity, postural imbalance, and falls that not only limit treatment, but also impact the quality of life for patients long into disease-free survival. These physical dysfunctions are commonly attributed to the degeneration of sensory nerves that disrupt distal sensations of touch, vibration and proprioception, termed ‘sensory neuropathy’. However, recent animal research has demonstrated that OX alters the proprioceptive information reaching the spinal cord and that these alterations occur independently from sensory neuropathy. These changes in the absence of sensory neuropathy can lead to substantial motor dysfunction in a rodent model with cancer. Unlike sensory neuropathy, these changes are not restricted to distal limbs but rather impair proximal and distal movement control. Furthermore, they occur before sensory neuropathy is present, suggesting that the current clinical measures for terminating OX treatment may not be sufficient for preventing motor impairments. It is not yet known if similar mechanisms of proprioceptive dysfunction are present in human cancer survivors treated with OX. This proposal will focus on this population, quantifying the time course of proprioceptive changes and comparing them to the evolution of sensory neuropathy. Cancer patients during the early, middle and late periods of OX treatments and age-matched healthy controls will be recruited. Aim 1 will quantify the conscious use of proprioception to generate volitional motions and forces. Aim 2 will quantify subconscious, involuntary motor actions (e.g. reflexes) generated in response to proprioceptive inputs. Both aims will use nerve conduction studies to monitor for signs of sensory neuropathy. OX-related changes in ability to perceive limb position and force, the size of reflex responses and the nerve conduction studies will be evaluated at different stages of OX treatment to determine if proprioceptive dysfunction exists separately from sensory neuropathy. This proposal will provide the first assessment of OX-induced proprioceptive dysfunction with respect to the development of sensory neuropathy in humans. The result will make a significant contribution toward determining if proprioceptive dysfunction contributes to motor impairments prior to the commonly assessed distal sensory neuropathy. Our work will be directly relevant to the current and future guidelines of dosing OX so as to minimize cancer-related physical dysfunction, and possibly for developing rehabilitation interventions to minimize the impact of OX treatments.