Deans

Michelle Clark, Ph.D. – College of Pharmacy Harold Laubach, Ph.D. – College of Medical Sciences

Award Date

1-1-2020

Abstract

Peripheral neuropathy (PN) affects 40% of all patients who receive chemotherapy for any cancer type, and its occurrence can lead to discontinuation of drug treatment. Interestingly, PN is one of the most common chemotherapy-induced side effects in Multiple myeloma (MM) patients. The pathogenesis of PN is not adequately known and needs further investigation since there is a lack of efficacious preventive options. Hence, it is imperative that we investigate and identify intervention points for treatment as well as for prevention of PN. Almost all MM patients who are receiving chemotherapy eventually progress to relapsed/refractory myeloma. Progression of the disease may occur earlier for some patients due to dose limitation and/or discontinuation of treatment owing to the severity of the side effects. Thus, chemotherapy-induced PN (CIPN) can be severe and debilitating, eventually impacting the quality of life in cancer patients. When CIPN gets very severe, adjustments to therapy are necessitated. These adjustments may include dosage reductions and suspensions or even discontinuation of the medication responsible for the adverse effects, which increases the likelihood of earlier disease progression. Anti-myeloma chemotherapy drugs such as bortezomib (BTZ) and thalidomide, despite being expedient targeted therapeutics, are typically implicated as primary causes of PN in MM patients. Among various remedies used for minimizing the deleterious effects of CIPN, Vitamin B12, Gamma linolenic acid (GLA), neuronal nitric oxide synthase (nNOS) inhibitors, and calcium channel blockers have a great potential to be utilized for improving CIPN outcomes and the quality of life and compliance during chemotherapy. However, there is a dearth of adequate studies to validate the benefits of potential complementary therapies. Therefore, this study is designed to evaluate the efficacy of certain neuroprotective (NP) treatments including vitamin B12, GLA, as well as the nNOS inhibitor (4S-N4-A-5A-Nʹ-nitroguanidine), the calcium channel blocker (Nimodipine) and glycogen synthase 3 (GSK-3) inhibitor (CHIR99021) in experimental models. Our study will investigate the intracellular mechanisms related to BTZ treatment that contribute to neuronal damage, and the usefulness of the aforementioned neuroprotectants in both the PC12 and Schwann cell neuronal models. A significant outcome of this project would be the identification of preventive and/or prophylactic treatment strategies that can help to alleviate suffering and positively impact the quality of life of MM patients who develop debilitating CIPN. Consequently, positive study findings would negate the need for medication adjustments and enable patients to receive the full benefit of chemotherapy.

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