Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of many commonly used chemotherapeutic agents, including platinum drugs and taxanes. CIPN, characterized by peripheral axonal degeneration and demyelination, can be disabling and extremely painful, causing significant loss of functional abilities and decreasing quality of life. Considering the incidence of CIPN vary from 30 to 40% of patients receiving chemotherapy, the total population affected by CIPN is enormous. Although some preventive strategies have been proposed to attenuate the development of CIPN, effective treatment of established CIPN has yet to be found. Therefore, a neurorestorative strategy to repair damaged axons is still critically needed to alleviate the symptom of established CIPN. Cognosci has innovatively created and characterized a series of peptides derived human apolipoprotein E (apoE), which are generally designated as COG compounds. Extensive studies have demonstrated that COG compounds exert potent anti-inflammatory activities, neuroprotective and neurorestorative activities both in vitro and in vivo. We have also obtained data showing that COG112, one of the most potent apolipoprotein E mimetics, can significantly prevent axonal degeneration and promote axonal regeneration and remyelination in a sciatic nerve crush model. A similar neuroprotective effect has been validated in animal models of a variety of neurological disorders such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage and multiple sclerosis, implicating a therapeutic efficacy for these diseases. Furthermore, Cognosci had successfully identified the binding protein of COG compounds, which is SET, an endogenous inhibitor of serine/threonine protein phosphatase 2A (PP2A). SET is well known as a nuclear oncogene and has been associated with several types of cancers, such as chronic lymphocytic leukemia (CLL), myeloid leukemia. With ongoing program to develop COG112 as anticancer drug, here we propose to examine whether COG112 can prevent the neuotoxicity of chemotherapies, repair histological damage and restore the lost functions of established CIPN in the following aspects: 1) Specific aim 1: To examine the potential neuroprotective and neuroregenerative effects of COG112 in a cisplatin and paclitaxel-induced axonal damage and neuronal cell death in primary dorsal root ganglion (DRG) cultures;2) Specific Aim 2: To examine if COG112 exerts neuroprotective and neurorestorative effects by histological and functional examination in a cisplatin-induced CIPN animal model.
The overall goal of this project is to obtain proof of concept that COG112 can be a therapeutic agent for chemotherapy induced peripheral neuropathy with dual favorable properties of neuroprotection and neurorestoration. Moreover, COG112 can either independently inhibit cancer growth or be combined with other anticancer drugs to enhance their therapeutic activity but to reduce their neurotoxic side effects. If substantiated by this study, COG112 may represent a promising therapy for both cancer and chemotherapy induced peripheral neuropathy.
|Li, Feng-Qiao; Fowler, Kenneth A; Neil, Jessica E et al. (2010) An apolipoprotein E-mimetic stimulates axonal regeneration and remyelination after peripheral nerve injury. J Pharmacol Exp Ther 334:106-15|