Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of widely used antitumoral agents in the taxane (e.g., paclitaxel), platinum-complex (e.g., oxaliplatin), vinca alkaloids (e.g., vincristine) &proteasome-inhibitor (e.g., bortezomib) classes.1-3 Thus, CIPN is one of most common causes of dose reduction &discontinuation of what is otherwise a life-saving therapy.2-7 Addressing this major public health issue by identifying therapeutic targets with immediate potential translation to the clinic is of paramount significance. We have identified A3 adenosine receptor (A3AR) agonism as a new viable therapeutic strategy for treating or reversing CIPN (Appendix 1 &ref8). Noteworthy, the selective A3AR agonists IB-MECA &its 2-chloro analogue (Cl-IBMECA) are in advanced clinical trials as antiinflammatory &antitumor agents.9,10 This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore the breadth of A3AR agonist applicability in CIPN while investigating underlying protective mechanism(s) of action. Using IB-MECA, three Specific Aims will test our central hypothesis: A3AR agonists are effective therapeutics in CIPN caused by chemotherapeutics with distinct antitumor mechanisms of action (paclitaxel, oxaliplatin &bortezomib) with beneficial effects exerted at the level of the peripheral sensory afferent (PSA) neuron &/or spinal cord.
In Aim 1, we will test if 1) IB-MECA blocks &reverses neuropathic pain, 2) the effects of IB-MECA are specific to an A3AR mediated mechanism using pharmacological &genetic knockout approaches, 3) potential central &peripheral site(s) of action underlie IB-MECA's action &4) IB-MECA prevents chemotherapy-evoked degeneration of intraepidermal nerve fibers &primary afferent spontaneous discharge.
In Aim 2, we will investigate the mechanism(s) whereby IB-MECA attenuates neuropathic pain through mitoprotective effects in PSA. Finally, in Aim 3, we will investigate if IB-MECA's effects include attenuating neuroinflammation &/or the dysregulation of glutamate homeostasis in the spinal cord, processes known to be essential to central sensitization. We will focus on NF?B &MAPK (ERK1/2, p38) signaling &glial-derived pro (TNF?, IL1?, &IL6)/anti (IL10)-inflammatory cytokines, as well as, the effects on the expression &activities of spinal glutamate transporters (neuronal &glial) &glial glutamine synthetase. If our hypothesis holds true, the outcome of our results are anticipated to provide the pharmacological rationale for """"""""proof-of-concept"""""""" for the use of selective A3AR agonists as a new approach in CIPN. From a translational perspective, this could conceivably lead to a """"""""fast track"""""""" investigation of IB-MECA for CIPN. This exciting possibility underscores the immediate clinical impact that our research proposal may have in this critical &unmet medical setting. Given the breadth of disorders impacted by A3AR agonists understanding their mechanism-based effects has far-reaching basic science &clinical implications.

Public Health Relevance

Chemotherapy-induced peripheral neuropathy (CIPN) with chronic neuropathic pain is the dose-limiting toxicity of many anti-neoplastics, reducing drug efficacy and patient quality of life. We have identified for the first time A3 adenosine receptor stimulation as a new therapeutic strategy to treat or reverse CIPN without compromising desirable antitumor effects. We will provide proof-of-concept data for this new approach to CIPN, the therapeutic impact of which cannot be overstated.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Alley, Michael C
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Saint Louis University
Schools of Medicine
Saint Louis
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Wahlman, Carrie; Doyle, Timothy M; Little, Joshua W et al. (2018) Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain 159:1025-1034
Tosh, Dilip K; Janowsky, Aaron; Eshleman, Amy J et al. (2017) Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters. J Med Chem 60:3109-3123
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Janes, Kali; Wahlman, Carrie; Little, Joshua W et al. (2015) Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A3 adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy. Brain Behav Immun 44:91-9
Tosh, Dilip K; Padia, Janak; Salvemini, Daniela et al. (2015) Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain. Purinergic Signal 11:371-87
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