Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side-effect arising in ~400,000 cancer patients yearly and often limits chemotherapy dosage. Pain and other quality of life impairments caused by CIPN are increasing as many forms of cancer become chronic conditions, with an estimated annual cost of ~$2.5 billion dollars (NCI Directors Consensus Workshop, June 2011). It has been assumed that as target-specific therapies were discovered, the off-target effect of peripheral neuropathy would lessen. However, as specific mechanism-based therapies (e.g. proteasome and Jak-2 inhibitors) have been introduced, the incidence of painful, chronic neuropathy has persisted at 30-40% of treated patients. Approaches to limit the impact of CIPN include prevention and symptomatic treatment of neuropathic pain. Preventive strategies are complicated by the risk that protection from CIPN may reduce the primary cancer cell killing effect of a drug. Symptomatic treatments for pain are frequently not successful, reflecting a lack of understanding of the underpinnings of neuropathic pain. In this application, the candidate proposes a comprehensive strategy to understand the biological mechanisms of CIPN caused by a specific chemotherapeutic drug (bortezomib) and the physiologic mechanisms underlying pain caused by the drug. The studies are expected to have broader implications for other diseases of the peripheral nervous system. The candidate is an M.D./Ph.D.-trained neurologist with advanced clinical training in peripheral nerve disorders whose career goal is to perform mechanistic and translational investigations of peripheral nerve disorders and neuropathic pain. Chemotherapy-induced peripheral neuropathy will be used as the model disease system to achieve this goal. The career development plan will be mentored by Dr. Anthony Windebank, a neuromuscular physician-scientist with expertise in CIPN, and Dr. Gianrico Farrugia whose lab focuses on structure-function studies of voltage-gated ion channels. The career development plan combines the strengths of the candidate, the mentors, and the research institution in order to provide an opportunity for the candidate to become a successful independent investigator of peripheral nerve disorders.
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side-effect that may limit chemotherapy dosage. Pain and other quality of life impairments caused by CIPN are increasing as many forms of cancer become chronic conditions. In this proposal, the candidate proposes to develop a comprehensive strategy to understand the biological mechanisms underpinning CIPN caused by a specific chemotherapeutic drug (bortezomib) and the physiologic mechanisms underlying pain caused by the drug.
|Shah, Arya; Hoffman, E Matthew; Mauermann, Michelle L et al. (2018) Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort. J Neurol Neurosurg Psychiatry 89:636-641|
|Staff, Nathan P; Grisold, Anna; Grisold, Wolfgang et al. (2017) Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol 81:772-781|
|Podratz, Jewel L; Kulkarni, Amit; Pleticha, Josef et al. (2016) Neurotoxicity to DRG neurons varies between rodent strains treated with cisplatin and bortezomib. J Neurol Sci 362:131-5|
|Johnson, Cassandra; Pankratz, Vernon S; Velazquez, Ana I et al. (2015) Candidate pathway-based genetic association study of platinum and platinum-taxane related toxicity in a cohort of primary lung cancer patients. J Neurol Sci 349:124-8|
|Staff, Nathan P; Amrami, Kimberly K; Howe, Benjamin M (2015) Magnetic resonance imaging abnormalities of peripheral nerve and muscle are common in amyotrophic lateral sclerosis and share features with multifocal motor neuropathy. Muscle Nerve 52:137-9|
|Hoffman, E Matthew; Staff, Nathan P; Robb, Jared M et al. (2015) Impairments and comorbidities of polyneuropathy revealed by population-based analyses. Neurology 84:1644-51|
|Chen, Bingkun K; Staff, Nathan P; Knight, Andrew M et al. (2015) A safety study on intrathecal delivery of autologous mesenchymal stromal cells in rabbits directly supporting Phase I human trials. Transfusion 55:1013-20|
|Piccione, Ezequiel A; Sletten, David M; Staff, Nathan P et al. (2015) Autonomic system and amyotrophic lateral sclerosis. Muscle Nerve 51:676-9|
|Staff, Nathan P; Windebank, Anthony J (2014) Peripheral neuropathy due to vitamin deficiency, toxins, and medications. Continuum (Minneap Minn) 20:1293-306|
|Staff, Nathan P; Dyck, P James B; Warner, Mark A (2014) Postsurgical inflammatory neuropathy should be considered in the differential diagnosis of diaphragm paralysis after surgery. Anesthesiology 120:1057|
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