Chemotherapy-induced peripheral neuropathy (CIPN) occurs in up to 75% of patients who receive cytotoxic agents such as paclitaxel (PTX), and is a major reason to discontinue chemotherapy. These patients experience pain, sensitivity to cold, and imbalance. PTX induces CIPN-related pain by activating Toll-like receptor 4 (TLR4) on monocytes, which induces expression of pro-inflammatory cytokines. Targeting TLR4 may be risky due to the role of TLR4 in immune defense against cancer. Interestingly, TLR4 activation triggers inositol-requiring enzyme 1 alpha-X-Box Binding Protein 1 (IRE1?-XBP1) signaling in immune cells. The inhibition of IRE1?-XBP1 enhances PTX antineoplastic effects by reducing pro-inflammatory factors, suggesting that it could be an attractive target to prevent CIPN and improve the efficacy of PTX for cancer. We have confirmed that PTX causes IRE1?-XBP1 activation and induces a pro-inflammatory phenotype in primary human leukocytes. Notably, leukocytes from mice lacking IRE1?-XBP1 specifically in immune cells (Ern1/Xbp1f/f-Vav1cre) do not display this pro-inflammatory phenotype upon PTX exposure. These conditional knockout (cKO) mice exhibit reduced cold allodynia and hind paw unbalance in a model of neuropathic pain (partial sciatic nerve ligation - PSNL). Additionally, through transcriptomic analyses we found that IRE1?-XBP1 signaling in leukocytes is critically required for the induction of prostanoids and cytokines that have been associated with CIPN. Therefore, we hypothesize that PTX promotes CIPN by activating IRE1?-XBP1 signaling in leukocytes, and that targeting this pathway could be used to prevent CIPN. We will accomplish the following specific aims: 1) Define the role of immune-intrinsic IRE1?-XBP1 in PTX-induced CIPN. We will administer PTX to mice with leukocyte-specific deletion of IRE1?-XBP1 (cKO) as well as their wild type (WT) counterparts. We anticipate that cKO mice will be protected from PTX-induced CIPN related behaviors. Then, we will treat WT mice with selective IRE1? inhibitors (MKC8866 or KIRA8) in order to pharmacologically prevent PTX-induced CIPN behaviors. These studies will define the feasibility and therapeutic potential of targeting IRE1? for CIPN. 2) Establish how PTX influences IRE1?-XBP1 signaling in immune cells to drive CIPN. We will exploit the ER stress-activated indicator (ERAI) transgenic mouse, whose cells express a yellow fluorescent protein variant (Venus) when IRE1? is activated. Immunofluorescence will be used to identify ER-stressed leukocytes in the blood, spleen, sciatic nerves, and dorsal root ganglia during CIPN. Leukocytes will be sorted according to reporter positivity and analyzed via RNA-Seq, immunophenotyping, and functional assays. These experiments will unearth how PTX- induced IRE1?-XBP1 activation influences leukocyte function throughout CIPN progression. Our team of neuro- oncologists, internist clinicians, and basic scientists with expertise in pain biology, neuroimmunology, immunology, cancer biology, IRE1?-XBP1, genomics and bioinformatics is uniquely positioned to test this innovative hypothesis and contribute to the development of novel non-narcotic treatments for chronic pain.

Public Health Relevance

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication in patients receiving cancer treatment with chemotherapeutic drugs and is characterized by long lasting numbness, tingling, cold hypersensitivity, and pain in hands and feet. These symptoms are severe and cause the cessation of chemotherapy treatment due to lack of effective therapies for CIPN. Thus, CIPN affects cancer patient?s quality of life and has a substantial economic and social impact. The proposed studies will provide the foundation for a new non-narcotic therapeutic strategy that has the potential to prevent CIPN.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Somatosensory and Pain Systems Study Section (SPS)
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Bakos, Alexis Diane
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Wake Forest University Health Sciences
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