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.
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.
|Trahan, Lisa H; Cox-Martin, Emily; Johnson, Carrie E et al. (2017) Psychometric Study of the Pain Drawing. J Appl Biobehav Res 22:|
|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|
|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 22:226-231|
|Dougherty, Patrick M (2016) Is Chemotherapy-induced Peripheral Neuropathy More Than Just a Peripheral Nervous System Disorder? Anesthesiology 124:992-3|
|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|
|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|
|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|
Showing the most recent 10 out of 40 publications