Therapy-induced peripheral neuropathy (TIPN) is a very common and often dose-limiting side effect of anti-cancer therapy. Clinically, TIPN is a predominantly sensory peripheral neuropathy characterized by numbness, tingling, and often, neuropathic pain. These symptoms can persist for years after cessation of treatment, and so TIPN can significantly diminish patient's quality-of-life both during and after treatment. Moreover, the development of TIPN often necessitates reducing drug dosage or switching regimens, and therefore limits the effectiveness of anti-cancer therapy. Currently, there are no effective treatments for TIPN. Axon loss is a hallmark of this neuropathy, suggesting that mechanistically distinct chemotherapeutics may feed into a common axonal degeneration program. We have demonstrated that genetic inhibition of SARM1, the central executioner of this core axonal degeneration program, blocks the development of TIPN in a mouse model of vincristine-induced peripheral neuropathy. The SARM1 pathway induces axon loss by triggering depletion of the essential metabolic co-factor NAD. Here we seek to block the development of TIPN by countering this loss of NAD in order to maintain axonal health. We also explore mechanisms to block the activation of SARM1 as novel therapeutic strategies for blocking the development of TIPN. Finally, targeting the SARM1 pathway will be a useful treatment for TIPN if manipulating this pathway does not affect tumor growth or chemotherapeutic efficacy. We will explore this using genetic tumor models. If successful, this project will identify novel treatment strategies for the prevention of TIPN.

Public Health Relevance

Therapy-induced peripheral neuropathy (TIPN) is the major dose limiting side effect of many common chemotherapeutics, impacting the efficacy of cancer treatment and the quality of life for cancer survivors. Loss of axons that connect neurons to their target is a hallmark of this neuropathy. We will develop methods to block the core axonal degeneration program in order to inhibit the loss of axons damaged by chemotherapy. The identification of methods to maintain axons may help ameliorate or prevent TIPN.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA219866-04
Application #
9978739
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Prasanna, Pat G
Project Start
2017-08-16
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Summers, Daniel W; Milbrandt, Jeffrey; DiAntonio, Aaron (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. Proc Natl Acad Sci U S A 115:E8746-E8754