(354) Repurposing Druggable Targets for the Treatment of Cancer Pain: A Translational Approach

Cancer cells secrete pro-nociceptive mediators into the microenvironment that sensitize sensory neurons and cause pain. We sought to identify protein encoding genes that drive nociception. We used a preclinical mouse model, transcriptomic analysis, and a proteomic literature review to undertake this work. Cancer cell line supernatant was assigned a phenotype based on evoked nociceptive behavior in a cancer pain mouse model. Mice received 50μl injections of supernatant in the tongue for 3 days followed by orofacial behavior assessment with a dolognawmeter 1 hour after the third injection. Data from the NCBI Gene Expression Omnibus was used to performdifferential gene expression and pathway analysis. We identified proteins potentially responsible for nociception using a literature review of the nociceptive cell lines. Mediator targets produced by these analyses were validated with the cancer pain mouse model. We identified 4 nociceptive and 4 non-nociceptive cell lines. We subsequently identified 1760 differentially expressed genes (DEG) and 14 significantly perturbed pathways by comparing the nociceptive and non-nociceptive cell lines. Thirty of 1760 DEG were reported in the literature to yield over-expressed proteins secreted or anchored to the plasma membrane in at least one of the nociceptive cell lines tested. For these 30 DEG, epidermal growth factor receptor (EGFR) was the most commonly cited druggable target (Drug–Gene Product Interaction Database). To determine if EGFR signaling is involved in cancer supernatant-induced nociception, we administered either EGFR antagonist, Cetuximab, or saline followed by nociceptive cell line supernatant injected into the mouse tongue. Mice that received saline exhibited significantly longer gnaw-time following injection of cancer supernatant (48.8±4.5%) compared to mice that received Cetuximab (13.8±11.8%). DEG and their secreted protein products may serve as therapeutic targets for cancer pain and warrant further evaluation.