Spinal cord stimulation for the attenuation of chemotherapy-induced peripheral neuropathy and enhanced chemotherapeutic efficacy

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Project Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment drugs that often presents as debilitating pain in a stocking-and-glove distribution. One plausible solution is spinal cord stimulation (SCS), a minimally invasive treatment used for refractory neuropathic pain conditions, yet the utility in CIPN pain treatment is unclear. SCS was historically thought to mediate pain inhibition via the gate-control theory, whereby electrical stimulation of the dorsal column activates Aβ afferents, which then inhibit nociceptive afferents (Aδ and C fibers); however, novel waveforms act independent of Aβ activation and a number of non-neuronal mechanisms have been proposed. Accordingly, the long-term goals of this application are to delineate the neuroimmune mechanisms of SCS-induced CIPN pain inhibition. The central hypothesis is that SCS can prevent CIPN pain and enhance chemo-efficacy. This hypothesis will be tested by pursuing three specific aims: 1) Determine the electrical parameters of SCS for prevention of painful CIPN and the underlying neuroimmune mechanisms in the rodent PNS. 2) Determine the vascular and immune mechanisms of SCS-enhanced chemo-efficacy in the tumor microenvironment of human non-small cell lung carcinoma (NSCLC). 3) Elucidate CIPN-associated mechanisms of neuronal hyperexcitability and neuropathic pain in human dorsal root ganglia (DRG). The proposed studies take advantage of state-of-the-art neuroscience tools (calcium imaging, electrophysiology) coupled with cancer-biology and neuroimmunology to delineate how SCS mediates CIPN pain inhibition and enhances paclitaxel efficacy. This work is significant with direct translational relevance since rational SCS parameter selection for CIPN pain treatment and improved chemo-efficacy will lead to improved patient outcomes. Dr. Eellan Sivanesan is a clinician-scientist whose career goals are to become an independently funded cancer pain researcher and a leader in the field of neuromodulation. Dr. Sivanesan will work closely with his mentorship team to develop expertise in cancer- biology, neuroimmunology, and cancer pain. This training will be accomplished primarily through hands-on experiments under supervision of his mentors, as well as structured didactic and non-didactic training, individualized instruction through regular meetings with his mentors, and systematic evaluations. Dr. Sivanesan will be conducting his research within Johns Hopkins University School of Medicine’s Department of Anesthesiology, a thriving academic, clinical, and research environment with exceptional facilities for early stage investigators.