Therapeutic Potential of Heat Shock Protein 27 on Chemotherapy-Induced Peripheral Neuropathy

(c) Abstract of Research comprehensible to a non-specialist:Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect associated with commonly used anti-cancer drugs such as Paclitaxel and Vincristine for treating ovarian, breast and stomach cancers. CIPN caused by peripheral nerve damage resulting in irreversible sensory and motor symptoms like numbness, allodynia, muscle weakness and loss of motor control which often compelling clinicians to discontinue this life saving treatment. Peripheral nerves (cord-like structure containing bundles of nerve fibers) connect our brain and spinal cord (central nervous system) to the limb and organs, and relay information to and from our brain. Peripheral nerve damage persists in CIPN patient since the usual slow recovery of damaged peripheral nerve does not always occur in CIPN. More than half of patients undergo Paclitaxel or Vincristine therapy develops irreversible CIPN, however, there is currently no prevention for CIPN. Therefore, there is an urge to develop potential preventive therapy for CIPN.What about the strategies to prevent cancer patients from developing CIPN? One way to achieve this is to enhance intrinsic growth capacity of neuron which protects them from possible peripheral nerve damage. We performed a study to address this and identified a growth-associated gene, a small heat shock protein (Hsp) 27. We showed that Hsp27 not only promotes sensory and motor functional recovery after a severe peripheral nerve injury, but also prevents development of key manifestations in a mouse model of type I diabetic neuropathy. More importantly, our preliminary data showed that peripheral neurons which overexpress human Hsp27 protects them against Paclitaxel and Vincristine inhibition on neurite extension (projection from peripheral neuron which makes up the nerve fibers). Based on these studies, we proposed that Hsp27 could be an effective preventive therapy for CIPN.In current proposal, we aim to address this hypothesis by using a CIPN animal model. CIPN animal model reproduces many human conditions which is widely used to study prevention and treatment of CIPN. We will treat mice overexpressing human Hsp27 in neuron with Paclitaxel and Vincristine, and perform animal behavioural studies to assess sensory and motor functional recovery. We also plan to use a high resolution atomic force microscopy to elucidate the protective mechanism of Hsp27 in CIPN. My ultimate goal is to combine chemotherapy agents with FDA approved molecule activating Hsp27 to prevent CIPN. This allows patient to continue their life-saving chemotherapy without suffering neurological side effects and improves quality of life.