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 This hypothesis is built upon unpublished preliminary data that we generated through an unbiased kinase inhibitor screen we performed to prevent chemotherapy induced neurotoxicity.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.