Peripheral neuropathy is the principal dose-limiting factor for each of the major frontline chemotherapeutic drugs used against all the most common types of cancer and hence affects hundreds of thousands of patients each year. Neuropathy causes such distress that many patients will drop out of potentially curative therapy, directly impacting their survival. Chemotherapy-induced pain is refractory to treatment and often persists in cancer survivors limiting quality of life, rehabilitation and the return to productivit. The continuing long-term goal of this project is to determine the mechanisms of chemotherapy- induced neuropathic pain (CIPN) and identify potential therapeutic interventions for its relief or prevention.
Three specific aims toward this goal will be tested in humans undergoing cancer therapy or in tumor-free animals receiving paclitaxel or oxaliplatin.
Specific Aim 1 will determine whether patient susceptibility to paclitaxel or oxaliplatin induced CIPN is dependent upon baseline innervation density of the extremities. The initial working hypothesis will be that patients who start with the lowest MC density in the fingertips or toes will be those most likely t develop CIPN.
Specific Aim 2 will determine whether activation of chemokine/cytokine signaling in the dorsal root ganglia are key early steps in peripheral mechanisms of paclitaxel and oxaliplatin induced chemoneuropathy. Behavioral, immunohistochemical, and biochemical approaches will be used to define the role of chemokine/cytokine signaling in the early as opposed to the mid- and late stages of both models of chemoneuropathy in rats. The initial working hypothesis is that MCP-1/CCR2 are key early mediators of paclitaxel CIPN whereas IL-6 is a late mediator. It is further hypothesized that similar cytokine mediators are key in oxaliplatin CIPN.
Specific Aim 3 will determine the second messenger systems that are recruited in the DRG in models of chemoneuropathy. Behavioral, immunohistochemical, and biochemical approaches will again be used. The initial working hypothesis is that the messengers associated with chemokine/cytokine signaling are the key signals. In summary this project will define mechanisms of chemotherapy-induced peripheral neuropathy, identify patient risk factors and potential new near-term protective and treatment candidates. This project will therefore impact on the quality of life, survival and the return to productivity of thousands of cancer patients who receive paclitaxel or oxaliplatin therapy.

Public Health Relevance

Peripheral neuropathy is the principal dose-limiting factor for each of the major frontline chemotherapeutic drugs used against all the most common types of cancer and hence affects hundreds of thousands of patients each year. Neuropathy causes such distress that many patients will drop out of potentially curative therapy, directly impacting their survival. This project will define mechanisms of chemotherapy-induced peripheral neuropathy;identify patient risk factors and potential new near-term protective and treatment candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046606-07
Application #
8475675
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Babcock, Debra J
Project Start
2003-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$367,459
Indirect Cost
$134,890
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Dougherty, Patrick M (2016) Is Chemotherapy-induced Peripheral Neuropathy More Than Just a Peripheral Nervous System Disorder? Anesthesiology 124:992-3
Zhang, Hongmei; Li, Yan; de Carvalho-Barbosa, Marianna et al. (2016) Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. J Pain 17:775-86
Shah, Nina; Shi, Qiuling; Williams, Loretta A et al. (2016) Higher Stem Cell Dose Infusion after Intensive Chemotherapy Does Not Improve Symptom Burden in Older Patients with Multiple Myeloma and Amyloidosis. Biol Blood Marrow Transplant 22:226-31
Mendoza, Tito R; Wang, Xin Shelley; Williams, Loretta A et al. (2015) Measuring Therapy-Induced Peripheral Neuropathy: Preliminary Development and Validation of the Treatment-Induced Neuropathy Assessment Scale. J Pain 16:1032-43
Li, Yan; Adamek, Pavel; Zhang, Haijun et al. (2015) The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4. J Neurosci 35:13487-500
Robinson, C R; Dougherty, P M (2015) Spinal astrocyte gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy. Neuroscience 285:1-10
Kim, Joyce H; Dougherty, Patrick M; Abdi, Salahadin (2015) Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy. Gynecol Oncol 136:453-9
Boyette-Davis, Jessica A; Walters, Edgar T; Dougherty, Patrick M (2015) Mechanisms involved in the development of chemotherapy-induced neuropathy. Pain Manag 5:285-96
Li, Yan; Zhang, Hongmei; Kosturakis, Alyssa K et al. (2015) MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy. Brain Behav Immun 49:255-66
Robinson, Caleb R; Zhang, Hongmei; Dougherty, Patrick M (2014) Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy. Brain Res 1574:6-13

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