Chemotherapy Induced Painful Neuropathy (CIPN) is one of the most significant problems afflicting cancer patients that are treated with various chemotherapeutic drugs. CIPN not only reduces cancer patient's quality of life, it often leads to withdrawal from potentially effective cancer therapy. Oxaliplatin is the third-generation of platinum chemotherapeutic drugs that is approved as the first line of treatment for metastatic colorectal cancer. Up to 20-30% of cancer patients that receive platinum agents develop pain and sensory changes, resulting in chronic dose-limiting CIPN. In addition, oxaliplatin induces distinctive acute cold-associated dysesthesia in up to 80% of patients. However, current treatments to reduce CIPN have only modest efficacy in most patients, are palliative rather than curative, and their side effects represent significant limitations. The goal of this proposal is to identify the regulated gene expression signaling pathways that control synaptic plasticity in CIPN and to determine whether brain-derived neurotrophic factor (BDNF)-trkB interactions mediate intracellular signaling cascades leading to persistent pain.
The aims of the proposal are: 1) To identify differences in the gene expression profiles in spinal dorsal horn (SDH) in CIPN mice compared to controls, and after trkB blocker treatment and, 2) To determine whether CIPN is accompanied by changes in the functional expression of BDNF and trkB in SDH. To accomplish these aims, the CIPN model will be generated in adult C57BL/6J male mice following oxaliplatin treatment. Affymetrix GeneChip(R) will be used to profile the expression of a large number of genes in the SDH in vivo to identify unique regulated gene expression signaling pathways in oxaliplatin-induced CIPN mice compared to control mice, and also following BDNF antagonist treatment. Animal behavioral testing will be used to characterize and quantify pain behavior in the experimental animals prior to isolation of tissue for microarray analysis. Immunohistochemistry will be used to validate and extend the microarray results and to determine whether CIPN alters BDNF functional expression in DRG and SDH. The outcome of the validated molecular determinants will provide potential targets for novel strategies to treat neuropathic pain. Key words: chronic pain, cancer pain, cancer prevention, chemoprevention, cisplatin, oxaliplatin, DNA microarray, gene expression profiling, in situ hybridization, molecular biology, neural plasticity, animal behaviors, mouse model Relevance: Successful cancer treatment is producing many long-term survivors and has led to increasing problems with chronic pain management. Understanding the mechanisms of chronic pain from chemotherapy treatment will provide important insights into therapeutic strategies which will also have general application in the field of pain management.
Successful cancer treatment is producing many long-term survivors and has lead to increasing problems with chronic pain management. Understanding the mechanisms of chronic pain from chemotherapy treatment will provide important insights into therapeutic strategies which will also have general application in the field of pain management.
| Pachman, Deirdre R; Loprinzi, Charles L; Grothey, Axel et al. (2014) The search for treatments to reduce chemotherapy-induced peripheral neuropathy. J Clin Invest 124:72-4 |
| Ta, Lauren E; Schmelzer, James D; Bieber, Allan J et al. (2013) A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy. PLoS One 8:e54161 |
| Podratz, Jewel L; Knight, Andrew M; Ta, Lauren E et al. (2011) Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis 41:661-8 |
