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

联合靶向 IL-6 和 EGFR 信号传导治疗神经鞘瘤病和相关疼痛

• 批准号: 10583903
• 负责人: JIANREN MAO
• 金额: $ 47.73万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583903
• 关键词: Adoptive Transfer; Afferent Neurons; Amplifiers; Bone Marrow; Cell Line; Clinical Trials; Compensation; Development; Disease; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Etiology; FDA approved; Genetic; Genetic Diseases; Goals; Growth; Infiltration; Inflammation; Inflammatory; Interleukin-6; Lesion; Ligands; Macrophage; Modeling; Molecular; Mus; Neurilemmoma; Neurons; Non-Malignant; Operative Surgical Procedures; Pain; Patients; Peripheral Nerves; Pharmaceutical Preparations; Production; Research; Risk; Role; Schwannomatosis; Sensory; Signal Transduction; Spinal Ganglia; Spinal nerve structure; Testing; Treatment Efficacy; Tumor-Derived; Vertebral column; chemokine; chronic pain; clinical translation; clinically relevant; combinatorial; curative treatments; cytokine; design; disability; efficacy evaluation; experimental study; improved; insight; loss of function; mouse model; nerve damage; neuronal tumor; neutralizing antibody; new therapeutic target; novel; novel therapeutics; pain reduction; patient derived xenograft model; pharmacologic; recruit; response; sciatic nerve; tumor; tumor growth

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.

摘要 神经鞘瘤病（SWN）是一种以多发性非恶性神经鞘瘤生长为特征的遗传性疾病 脊椎和周围神经的损伤SWN患者绝大多数表现为顽固性、衰弱性 慢性疼痛严重到足以导致永久性残疾SWN疼痛的病因尚不清楚， SWN和相关疼痛的新治疗方法的开发非常缓慢和低效。治疗 对于SWN，仅限于侵入性手术，这具有进一步神经损伤的显著风险。目前没有药物 FDA批准停止SWN肿瘤生长或改善SWN相关疼痛。认识到世界上最大的 SWN研究的挑战是缺乏临床相关模型，我们成功地建立了患者源性 SWN细胞系，并将其在原位坐骨神经和脊柱小鼠模型中生长， 诱发疼痛。使用这些新型患者来源的异种移植模型（PDX），在初步研究中，我们发现： i）在周围神经中生长的肿瘤病变引起巨噬细胞流入背根神经节 (DRG)ii）SWN肿瘤衍生的高迁移率族蛋白盒1（HMGB 1），一种关键的炎症引发剂，以及 放大器，调节C-C基序趋化因子配体2（CCL 2）的神经元表达，CCL 2是关键的巨噬细胞 趋化因子，iii）肿瘤引发的巨噬细胞产生升高水平的促炎细胞因子， 白细胞介素-6（IL-6），iv）IL-6中和抗体显著降低疼痛反应，但对 抗IL-6治疗激活EGFR信号传导， 可以补偿肿瘤的生长。基于这些令人兴奋的发现，我们假设：i）SWN衍生 HMGB 1刺激感觉神经元表达CCL 2，CCL 2将巨噬细胞募集到DRG中，ii） 巨噬细胞通过IL-6的过度产生引起疼痛反应，和iii）IL-6和EGFR的联合阻断可以 在SWN模型中同时减轻疼痛和抑制肿瘤生长。在目标1中，使用原位SWN PDX 模型，我们将进行功能丧失实验，以评估肿瘤来源的HMGB 1在肿瘤中的功能作用。 调节神经元中CCL 2的表达。然后，我们将研究神经元（CCL 2）-巨噬细胞（CCR 2）轴是否是 在巨噬细胞募集和疼痛反应中至关重要，使用骨髓源性过继转移 来自Ccr 2-/-小鼠的巨噬细胞。在目标2中，使用遗传沉默和药理学抑制，我们将评估 肿瘤源性与巨噬细胞源性IL-6信号传导对原位SWN中疼痛反应的贡献 此外，我们将确定IL-6中和抗体在减轻疼痛反应中的功效。 在目标3中，我们将测试IL-6和EGFR联合阻断在延迟肿瘤生长方面有效的假设。 生长和减少疼痛反应。影响：如果成功，本研究将i） 为肿瘤（HMGB 1）-神经元（CCL 2）- 巨噬细胞（IL-6）串扰引起SWN疼痛，和ii）使用FDA批准的IL-6和EGFR抑制剂 以同时减轻SWN中的疼痛并控制肿瘤生长。