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 peripheral neuropathy (CIPN) is refractory to treatment and often persists in cancer survivors limiting quality of life, rehabilitation and the return to productivity. The continuing long-term goal of this project is to determine the mechanisms of CIPN and identify potential therapeutic interventions for its relief or prevention. The main hypothesis in this project is that chemotherapeutics activate toll-like receptor 4 (TLR4) on subsets of DRG neurons that 1) trigger altered cellular signaling in DRG neurons and infiltration of the DRG by immune cells that initiate and sustain CIPN; 2) drive the loss of distal epidermal nerve fibers (ENFs) to a critical point associated with onset of CIPN symptoms; and 3) cause activation of spinal glia and neurons that result in maladaptive changes in the physiology of these cells that further contribute to CIPN symptoms. This hypothesis will be tested in humans and animals that receive chemotherapy treatments.
Specific Aim 1 will determine whether activation of innate immunity in the DRG is a key initiating step in CIPN.
Specific Aim 2 will determine whether CIPN in humans is triggered when peripheral innervation density decreases to a critical point during chemotherapy.
Specific Aim 3 will determine the role of TLR4 and damage associated molecular pattern (DAMP) proteins in driving maladaptive plasticity in the spinal dorsal horn contributing to CIPN. 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.

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 Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA200263-01A1
Application #
9125972
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xie, Heng
Project Start
2016-05-09
Project End
2021-04-30
Budget Start
2016-05-09
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Illias, Amina M; Gist, Andrea C; Zhang, Haijun et al. (2018) Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity. Pain 159:1308-1316
Zhang, Hongmei; Li, Yan; Yang, Qing et al. (2018) Morphological and Physiological Plasticity of Spinal Lamina II GABA Neurons Is Induced by Sciatic Nerve Chronic Constriction Injury in Mice. Front Cell Neurosci 12:143
Li, Yan; North, Robert Y; Rhines, Laurence D et al. (2018) DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain. J Neurosci 38:1124-1136
Trahan, Lisa H; Cox-Martin, Emily; Johnson, Carrie E et al. (2017) Psychometric Study of the Pain Drawing. J Appl Biobehav Res 22:
Paice, Judith A; Mulvey, Matt; Bennett, Michael et al. (2017) AAPT Diagnostic Criteria for Chronic Cancer Pain Conditions. J Pain 18:233-246
Vedantam, Aditya; Hou, Ping; Chi, T Linda et al. (2017) Use of Spinal Cord Diffusion Tensor Imaging to Quantify Neural Ablation and Evaluate Outcome after Percutaneous Cordotomy for Intractable Cancer Pain. Stereotact Funct Neurosurg 95:34-39
Vedantam, A; Hou, P; Chi, T L et al. (2017) Postoperative MRI Evaluation of a Radiofrequency Cordotomy Lesion for Intractable Cancer Pain. AJNR Am J Neuroradiol 38:835-839
Cox-Martin, Emily; Trahan, Lisa H; Cox, Matthew G et al. (2017) Disease burden and pain in obese cancer patients with chemotherapy-induced peripheral neuropathy. Support Care Cancer 25:1873-1879
Li, Yan; Tatsui, Claudio Esteves; Rhines, Laurence D et al. (2017) Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy. Pain 158:417-429
Abdi, Salahadin; Dougherty, Patrick M (2016) Chemotherapy-Induced Peripheral Neuropathy: A Challenge for Clinicians. Oncology (Williston Park) 30:1030, C3

Showing the most recent 10 out of 18 publications