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IRE1a-XBP1 Signaling as a Driver of Chemotherapy-Induced Peripheral Neuropathy

Award Number: R21CA248106
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2022

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IRE1a-XBP1 Signaling as a Driver of Chemotherapy-Induced Peripheral Neuropathy - Summary 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 (IRE1α-XBP1) signaling in immune cells. The inhibition of IRE1α-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 IRE1α-XBP1 activation and induces a pro-inflammatory phenotype in primary human leukocytes. Notably, leukocytes from mice lacking IRE1α-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 IRE1α-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 IRE1α-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 IRE1α-XBP1 in PTX-induced CIPN. We will administer PTX to mice with leukocyte-specific deletion of IRE1α-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 IRE1α inhibitors (MKC8866 or KIRA8) in order to pharmacologically prevent PTX-induced CIPN behaviors. These studies will define the feasibility and therapeutic potential of targeting IRE1α for CIPN. 2) Establish how PTX influences IRE1α-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 IRE1α 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 IRE1α-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, IRE1α-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$6,047 )
2023	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	-$6,047
														Subtotal = -$6,047

Issue Date FY: 2022 ( Subtotal = -$20,513 )
2022	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	2	9/14/2022	NON-COMPETING CONTINUATION	-$20,513
														Subtotal = -$20,513

Issue Date FY: 2021 ( Subtotal = $185,221 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	2	4/16/2021	NON-COMPETING CONTINUATION	$185,221
														Subtotal = $185,221

Issue Date FY: 2020 ( Subtotal = $234,309 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	1	2/28/2020	NEW	$234,309
														Subtotal = $234,309

Grand Total All Awards = $392,970

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IRE1a-XBP1 Signaling as a Driver of Chemotherapy-Induced Peripheral Neuropathy

Award Number: R21CA248106

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2022

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