Lung cancer is currently a leading cause of mortality. One of these serious neurotoxic side effects that develop in lung cancer patients receiving chemotherapeutic agents is chemotherapy-induced peripheral neuropathy (CIPN). Our proposal will be focused on CIPN induced by cisplatin and paclitaxel since these are two of the most effective and widely used chemotherapy drugs in the treatment of common cancers, including non- small cell lung cancer. CIPN can be a dose-limiting factor for chemotherapy or result in premature termination of treatment, thereby influencing survival and quality of life. Currently, there are no effective therapies that deal with the underlying pathogenic mechanisms such as neurodegeneration. In addition, the current symptomatic therapies that deal with painful symptoms of CIPN are generally ineffective. Therefore, the identification of alternative forms of therapy is a crucial medical need. In this application we will focus on nicotinic acetylcholine receptors (nAChRs) modulators, in particular ?7 subtypes, as potential targets for treatment of CIPN. These receptors are expressed by central and peripheral neuronal cells (dorsal root ganglia) involved in pain transmission and by macrophages and other cells involved in the inflammatory responses.
In Aim 1, we will test the ability of ?7 nAChR silent agonists to prevent or ameliorate the development of peripheral neuropathy induced by cisplatin and paclitaxel, including well- defined neuropathologies that accompany CIPN.
In Aim 2, we will test the ?7 nAChR silent agonists in non-small cell lung cancer cell lines and patient derived tumor cells in culture as well as in tumor bearing mice to eliminate the possibility that these agents stimulate tumor growth or compromise the potency of chemotherapy (cisplatin and paclitaxel). In addition, suppression of CIPN by the ?7 nAChR silent agonists will be confirmed in the tumor bearing mice. If effective treatment/prevention can be identified, it should be possible to treat patients or prolonged periods as dose-dependent neuropathy will not be a limiting toxicity and compliance as well as quality of life will be improved.

Public Health Relevance

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and often dose- limiting complication of cancer therapy utilizing taxanes, platinum based drugs and newer agents such as bortezomib. Determining the modulatory role of a novel group of compounds known as ?7 silent agonists at nicotinic acetylcholine receptors in chemotherapy-induced peripheral neuropathy represents a unique strategy for the development of treatments for prevention and/or reversal of CIPN. If successful, this application promises to have a significant positive impact on compliance and symptom management for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA206028-03
Application #
9452918
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Alley, Michael C
Project Start
2016-04-15
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Wodarski, Rachel; Bagdas, Deniz; Paris, Jason J et al. (2018) Reduced intraepidermal nerve fibre density, glial activation, and sensory changes in HIV type-1 Tat-expressing female mice: involvement of Tat during early stages of HIV-associated painful sensory neuropathy. Pain Rep 3:e654
Bagdas, D; Meade, J A; Alkhlaif, Y et al. (2018) Effect of nicotine and alpha-7 nicotinic modulators on visceral pain-induced conditioned place aversion in mice. Eur J Pain :
Kyte, S Lauren; Toma, Wisam; Bagdas, Deniz et al. (2018) Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN. J Pharmacol Exp Ther 364:110-119
Bagdas, D; Ergun, D; Jackson, A et al. (2018) Allosteric modulation of ?4?2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain. Eur J Pain 22:84-93
Kyte, S Lauren; Gewirtz, David A (2018) The Influence of Nicotine on Lung Tumor Growth, Cancer Chemotherapy, and Chemotherapy-Induced Peripheral Neuropathy. J Pharmacol Exp Ther 366:303-313
Bagdas, Deniz; Gurun, Mine S; Flood, Pamela et al. (2018) New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on ?7 nAChRs. Curr Neuropharmacol 16:415-425
Curry, Zachary A; Wilkerson, Jenny L; Bagdas, Deniz et al. (2018) Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy. J Pharmacol Exp Ther 366:169-183
Donvito, Giulia; Bagdas, Deniz; Toma, Wisam et al. (2017) The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-? represents a new antinociceptive signaling pathway in mice. Exp Neurol 295:194-201
Toma, Wisam; Kyte, S Lauren; Bagdas, Deniz et al. (2017) Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse. Neuropharmacology 117:305-315
Donvito, Giulia; Wilkerson, Jenny L; Damaj, M Imad et al. (2016) Palmitoylethanolamide Reverses Paclitaxel-Induced Allodynia in Mice. J Pharmacol Exp Ther 359:310-318