Research Project
10199955
Abstract: Platinum-based drugs are commonly used to treat cancers. Platinum drugs are the first line therapy for ovarian and colorectal cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common complications. More than 70% of the patients receiving oxaliplatin are affected by neuropathy. Oxaliplatin induces two symptoms of peripheral sensory neuropathy; an acute and transient cold-aggravated, and a chronic form that has onset after multiple exposures to the drug and does not disappear with drug cessation. The neurotoxicity often leads to platinum drug dose reductions, compromising efficiency of platinum drugs to suppress tumor progression. On an average of 6 years after chemotherapy, 47% of women still reported symptoms of CIPN. Studies to develop a neuroprotective agent have, to date, been unsuccessful to reduce CIPN. There is an imperative need to develop new therapies to CIPN. Challenges to develop such therapies include that a therapy needs not to impede antitumor efficacy, but to effectively inhibit CIPN. Our preliminary data demonstrated cerebral endothelial cell derived exosomes (CEC-exos) abolish oxaliplatin- induced peripheral neuropathy in tumor bearing mice and sensitize oxaliplatin on cancer cell killing. Exosomes are nanovesicles and mediate intercellular communication by transferring cargo proteins, lipids, and genomic materials including mRNAs and microRNAs (miRNAs) between source and target cells. We found that treatment of the tumor bearing mice with CEC-exos along with oxaliplatin induces a network of miRNAs/mRNAs in sciatic nerves that exerts neuroprotection in sciatic nerves and DRG neurons, but triggers a distinct miRNAs/mRNAs network in tumor to promote cancer cell death. We, thus, hypothesized that CEC- exos mitigate peripheral neurotoxicity induced by platinum drugs and that CEC-exos enhance the anti- cancer efficacy of platinum drugs on tumor cells. Three specific aims are proposed to test this overall hypothesis. Aim 1 is to investigate the efficacy of the CEC-exos on ameliorating platinum drug-induced peripheral neurotoxicity and on improving the treatment of tumor. Aim 2 is to investigate molecular mechanisms underlying the therapeutic effect of CEC-exos on platinum drug-induced peripheral neuropathy with a focus on the interaction between CEC exosomal miRNAs and their target proteins in axons and DRG neurons. Aim 3 is to investigate molecular mechanisms underlying the effect of CEC-exos on sensitizing tumors to platinum drugs with a focus on the interaction between CEC exosomal miRNAs and their target proteins in tumor cells. Accomplishing these aims will potentially lead to development of a new CEC-exo based therapy for CIPN, leading to improvement in the quality of life and possibly cure of cancers.
