Oxaliplatin-associated Chemotherapy-induced Peripheral Neuropathy (CIPN) is a frequent, potentially severe and dose-limiting toxicity of colorectal cancer treatment. The overall incidence of CIPN is estimated to be approximately upwards of 40% in patients. CIPN can persist for months to years beyond chemotherapy completion, causing significant challenges for cancer survivors due to its negative influence on quality of life (QOL). CIPN represents an important challenge because of the lack of treatment that can effectively prevent or mitigate this adverse drug effect. We have identified specific receptor-mediated pathways which contribute to increases in ion current as a potential therapeutic target for the treatment or prevention of CIPN. Noteworthy, several ion channel modulators central to CIPN treatment are FDA-approved drugs used for other disease conditions. This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore both the mechanism of CIPN and the degree to which FDA-approved drugs can be repurposed for the treatment or prevention of the condition.
In Aim 1, we will examine the influence of platinum-DNA adducts and release of high mobility group box-1 (HMGB1) in rodents following exposure to oxaliplatin.
In Aim 2, we will investigate whether the receptor Toll-like receptor (TLR4) is responsible for the development or maintenance of CIPN across time. Finally, in Aim 3, we will conduct a proof of concept assessment of the efficacy of FDA-approved antiepileptic drugs on both neuronal ion currents and CIPN behavioral characteristics. These proposed studies will provide new therapeutic targets which will likely alter the detrimental effects of oxaliplatin on sensory neurons.

Public Health Relevance

The overall goal of this proposal is to determine the mechanism(s) that contribute to oxaliplatin?associated chemotherapy-induced peripheral neuropathy (CIPN) in the rodent. Determination of the compound-substrate mode of action is of paramount importance for both new drug development and possible repurposing of FDA-approved antiepileptic drugs for treatment of clinical CIPN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS102415-01A1
Application #
9603972
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Oshinsky, Michael L
Project Start
2018-09-15
Project End
2023-06-30
Budget Start
2018-09-15
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202