# MAP4K4 inhibition to prevent CIPN

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $450,313

## Abstract

Project Summary
 Peripheral neuropathies are major neurological complications of multiple chemotherapy drugs
causing significant morbidity affecting quality of life and potentially altering life-saving chemotherapy
regimens. Many chemotherapy drugs with diverse mechanisms of actions cause axonal degeneration and
the underlying mechanisms that lead to distal axonal degeneration, a common feature of most peripheral
neuropathies, are poorly understood. Furthermore, currently there are no therapies aimed at preventing,
reversing, or slowing the progression of peripheral neuropathies that cause chronic neuropathic pain,
sensory loss, and weakness.
 In this exploratory R21 grant we will test the overall hypothesis that MAP4K4 inhibition protects
peripheral sensory neurons against toxicity of several chemotherapy drugs and prevents chemotherapy-
induced peripheral neuropathy (CIPN). This hypothesis is built upon unpublished preliminary data that we
generated through an unbiased kinase inhibitor screen we performed to prevent chemotherapy induced
neurotoxicity. In these preliminary studies we found that PF-06260933 dihydrochloride (PF062), a MAP4K4
inhibitor, provided robust protection against neurotoxicity of Paclitaxel (PTX), and Cisplatin (CDDP) and
Bortezomib (BTZ) in vitro. These studies suggest that axon degeneration cascades initiated by three
chemotherapy drugs with different mechanisms of action (paclitaxel, cisplatin, and bortezomib) converge
on MAP4K4 and that inhibitors of MAP4K4 can be used to prevent neurotoxicity of different chemotherapy
drugs.
 We propose to test this hypothesis further by validating the neuroprotective effects of MAP4K4
inhibitors from different chemical classes as well as using genetic knockdown experiments. Furthermore,
we will test the role of MAP4K4 inhibition in vivo. Completion of these studies will give us a better
understanding of the role of MAP4K4 in distal axonal degeneration in CIPN and help further explore a novel
therapeutic target that can be taken to clinical studies in a timely manner.

## Key facts

- **NIH application ID:** 10987105
- **Project number:** 1R21NS135481-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ahmet Hoke
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $450,313
- **Award type:** 1
- **Project period:** 2024-06-21 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987105

## Citation

> US National Institutes of Health, RePORTER application 10987105, MAP4K4 inhibition to prevent CIPN (1R21NS135481-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10987105. Licensed CC0.

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