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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA169519-01A1
Application #
8501971
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Alley, Michael C
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$312,246
Indirect Cost
$102,555
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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
Romero-Reyes, M; Salvemini, D (2016) Cancer and orofacial pain. Med Oral Patol Oral Cir Bucal 21:e665-e671
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
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
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
Trang, Tuan; Al-Hasani, Ream; Salvemini, Daniela et al. (2015) Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics. J Neurosci 35:13879-88
Janes, Kali; Esposito, Emanuela; Doyle, Timothy et al. (2014) A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways. Pain 155:2560-7

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