Co-Targeting IL-6 and EGFRsignaling for the Treatment of Schwannomatosis and Associated Pain

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ABSTRACT Schwannomatosis (SWN) is a genetic disorder characterized by multiple non-malignant schwannomas growing on the spine and peripheral nerves. Patients with SWN overwhelmingly present with intractable, debilitating chronic pain, severe enough to cause permanent disability. The etiology of pain in SWN is not clear and the development of novel treatments for SWN and related pain has been extremely slow and inefficient. Treatment for SWN is limited to invasive surgery, which carries significant risk of further nerve damage. No drug is currently FDA-approved to halt SWN tumor growth or ameliorate SWN-associated pain. Recognizing that one of the biggest challenges in SWN research is the lack of clinically-relevant models, we successfully established patient-derived SWN cell lines and grew them in the orthotopic sciatic nerve and spine mouse models that reproduce tumor- induced pain. Using these novel patient-derived xenograft models (PDX), in preliminary studies, we found that: i) tumor lesions that grew in the peripheral nerve cause an influx of macrophage into the dorsal root ganglia (DRG), ii) SWN tumor-derived Highly Mobility Group Box1 (HMGB1), a key inflammation initiator and amplifier, regulates neuronal expression of C-C motif chemokine ligand 2 (CCL2), the key macrophage chemokine, iii) tumor-primed macrophages produce elevated levels of the pro-inflammatory cytokine, Interleukin-6 (IL-6), iv) IL-6 neutralizing antibody significantly reduces pain response but had little efficacy on tumor growth in the orthotopic SWN PDX model, and v) anti-IL-6-treatment activates EGFR signaling, which can compensate for tumor growth. Based on these exciting discoveries, we hypothesize that: i) SWN-derived HMGB1 stimulates sensory neurons to express CCL2, which recruits macrophages into the DRG, ii) macrophages cause pain response via overproduction of IL-6, and iii) combined IL-6 and EGFR blockade can concurrently reduce pain and inhibit tumor growth in SWN models. In Aim 1, using orthotopic SWN PDX models, we will perform loss-of-function experiments to assess the functional role of tumor-derived HMGB1 in regulating CCL2 expression in neurons. Then, we will study if the neuron (CCL2)-macrophage (CCR2) axis is essential in macrophage recruitment and pain response, using the adoptive transfer of bone marrow-derived macrophage from Ccr2-/- mice. In Aim 2, using genetic silencing and pharmacologic inhibition, we will assess the contributions of tumor-derived vs. macrophage-derived IL-6 signaling on pain response in orthotopic SWN PDX models; moreover, we will determine the efficacy of IL-6 neutralizing antibody in reducing pain response. In Aim 3, we will test the hypothesis that combined IL-6 and EGFR blockade is effective in delaying tumor growth and reducing pain response in orthotopic SWN PDX models. Impact: If successful, this study will i) provide pivotal cellular and molecular mechanistic insights into the role of tumor (HMGB1)–neuron (CCL2)– macrophage (IL-6) crosstalk in causing pain in SWN, and ii) employ FDA-approved IL-6 and EGFR inhibitors to simultaneously alleviate pain and control tumor growth in SWN.