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.
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.
|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|
|Janes, K; Symons-Liguori, A M; Jacobson, K A et al. (2016) Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics. Br J Pharmacol 173:1253-67|
|Carlin, Jesse Lea; Tosh, Dilip K; Xiao, Cuiying et al. (2016) Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors. J Pharmacol Exp Ther 356:474-82|
|Romero-Reyes, M; Salvemini, D (2016) Cancer and orofacial pain. Med Oral Patol Oral Cir Bucal 21:e665-e671|
|Tosh, Dilip K; Ciancetta, Antonella; Warnick, Eugene et al. (2016) Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists. J Med Chem 59:3249-63|
|Ford, Amanda; Castonguay, Annie; Cottet, Martin et al. (2015) Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain. J Neurosci 35:6057-67|
|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|
|Little, Joshua W; Ford, Amanda; Symons-Liguori, Ashley M et al. (2015) Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 138:28-35|
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