Chemotherapy-induced peripheral neuropathy (CIPN) is the most unwanted aspect of chemotherapy during cancer treatment. Painful CIPN not only affects patients’ quality of life, but often leads to termination of life saving chemotherapy. Currently there is no therapeutic strategies to prevent painful CIPN development. The conventionally used opioids and antidepressants have limited success. Hence, it is crucial to reveal mechanisms controlling development of painful CIPN. We revealed a novel immune regulator, lymphotoxin beta receptor (LTbR) as critical molecule controlling the development of CIPN pain in mice. Importantly, pharmacological inhibition of LTbR prevented the development of CIPN p...

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Chemotherapy-induced peripheral neuropathy (CIPN) is the most unwanted aspect of chemotherapy during cancer treatment. Painful CIPN not only affects patients’ quality of life, but often leads to termination of life saving chemotherapy. Currently there is no therapeutic strategies to prevent painful CIPN development. The conventionally used opioids and antidepressants have limited success. Hence, it is crucial to reveal mechanisms controlling development of painful CIPN. We revealed a novel immune regulator, lymphotoxin beta receptor (LTbR) as critical molecule controlling the development of CIPN pain in mice. Importantly, pharmacological inhibition of LTbR prevented the development of CIPN pain. The objectives of this proposal are to define the role of LTbR specifically in sensory neurons and develop novel therapeutic strategy to block CIPN pain. Our central hypothesis is that LTbR signaling in sensory neurons is critical for the development and maintenance of CIPN pain and that therapeutic targeting of LTbR inhibits CIPN pain. This hypothesis will be tested in two aims. In Aim 1 we will generate mice with specific inactivation of LTbR in sensory neurons and evaluate CIPN pain responses. Further, we will use neuron labeling approach to define critical LTbR-dependent genes and signaling pathways in sensory neurons. In Aim 2, we will evaluate the effect of intrathecal LTbR antagonist treatment on CIPN pain and sensory neuronal excitability. Our interdisciplinary team have expertise in immunology and neuroscience and is uniquely qualified to accomplish this project. The proposed research is significant for patients with cancer as it advances our understanding of immune mechanisms regulating development of CIPN pain; offers novel immune target, LTbR, and an immunotherapeutic approach for prevention and treatment of painful CIPN. Therefore, we believe that the proposed research will have critically positive impact on cancer patients undergoing chemotherapy.

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