Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequent cause of dose reduction or treatment discontinuation in patients treated for cancer with commonly used drugs such as taxanes and platinum-based compounds. Patients with CIPN report loss of peripheral sensory sensitivity, tingling, and pain separately or in combination in a 'stocking and glove'distribution. The incidence of this toxicity is anticipated t increase as newer drugs like proteasome inhibitors and targeted therapies are also frequently leading to CIPN. Recent estimates indicate that several hundred thousand patients suffer from CIPN each year and the dose limiting effects of this toxicity are likely to impact survival. In addition, peripheral neuropathy has a major impact on quality of life. There are no FDA-approved treatments for CIPN and the underlying mechanisms are only begun to be understood. Rodent studies implicate neural mitochondrial damage in the pathophysiology of CIPN. We have shown that inhibition of the accumulation of the pro-apoptotic factor p53 or inhibition of activation of the stress kinase c-Jun N-terminal Kinase (JNK) specifically at the mitochondria protects cerebral neuronal mitochondrial integrity and reduces neuronal loss in a model of ischemic brain damage. Here we propose to apply this knowledge to the prevention of CIPN. Our working hypothesis is that local targeting of JNK activation or p53 accumulation at the mitochondria in peripheral neurons will prevent development of CIPN. To test our hypothesis we will pursue the following three specific aims: 1: Determine the effect of local targeting of mitochondrial JNK/P53 on paclitaxel-induced mechanical hyperalgesia and verify that it does not interfere with cancer therapy 2: Inhibit the JNK/p53 pathway to protect against sensorimotor dysfunction and loss of paw innervation;3: Investigate the cell biological mechanisms contributing to the protective effects of local treatment. This research application is innovative because: (a) the mitochondrial P53/JNK pathway in peripheral neurons has not been targeted to protect against chemotherapy-induced neuronal damage and peripheral neuropathy;this novel target is likely to open up a new range of therapeutic means for preventing CIPN. (b) Successful completion of this study will not only open novel therapeutic options but also provide behavioral tests for assessing sensorimotor deficits in rodents. These tests will allow answering the question whether the same or distinct molecular mechanisms underlie pain and sensorimotor deficits that are characteristic of CIPN. (c) Until now, rodent studies treating CIPN mostly ignored potential interference with cancer therapy. We plan to analyze a potential interference of drug treatment in vivo as well as in vitro using p53 positive and negative tumors. This project is significant because it will likely lead to development of novel interventions for prevention of CIPN, still the major dose-limiting toxicity in patients treated for cancer. Mitochondrial damage i probably also at the origin of peripheral diabetic neuropathy and contributes to other forms of neuropathic pain, so the expected findings should benefit this large population of patients as well.
The proposed research is relevant and significant for public health because we anticipate identification of novel therapeutic targets to treat chemotherapy-induced peripheral neuropathy (CIPN), a major cause of dose reduction and treatment interruption in patients treated for cancer. Based on our recent findings on neuronal and mitochondrial protection in animal models of brain damage, we propose to locally target neuronal mitochondrial pathways that are activated by chemotherapeutic agents. The proposed project responds directly to PA-13-119, Mechanisms, Models, Measurement and Management in Pain Research and is relevant to the mission of the NCI that includes supporting research on the continuing care of cancer patients.
|Chiu, Gabriel S; Maj, Magdalena A; Rizvi, Sahar et al. (2017) Pifithrin-? Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function. Cancer Res 77:742-752|
|Maj, Magdalena A; Ma, Jiacheng; Krukowski, Karen N et al. (2017) Inhibition of Mitochondrial p53 Accumulation by PFT-? Prevents Cisplatin-Induced Peripheral Neuropathy. Front Mol Neurosci 10:108|
|Dantzer, Robert (2017) Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. Curr Top Behav Neurosci 31:117-138|
|Krukowski, Karen; Ma, Jiacheng; Golonzhka, Olga et al. (2017) HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain 158:1126-1137|
|Krukowski, Karen; Eijkelkamp, Niels; Laumet, Geoffroy et al. (2016) CD8+ T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain. J Neurosci 36:11074-11083|
|LaVoy, Emily C P; Fagundes, Christopher P; Dantzer, Robert (2016) Exercise, inflammation, and fatigue in cancer survivors. Exerc Immunol Rev 22:82-93|
|Zhou, Wenjun; Kavelaars, Annemieke; Heijnen, Cobi J (2016) Metformin Prevents Cisplatin-Induced Cognitive Impairment and Brain Damage in Mice. PLoS One 11:e0151890|
|Krukowski, Karen; Nijboer, Cora H; Huo, XiaoJiao et al. (2015) Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor pifithrin-?. Pain 156:2184-92|
|Vichaya, Elisabeth G; Chiu, Gabriel S; Krukowski, Karen et al. (2015) Mechanisms of chemotherapy-induced behavioral toxicities. Front Neurosci 9:131|