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.

抽象的 神经鞘瘤病（SWN）是一种遗传性疾病，其特征是多发性非恶性神经鞘瘤生长 绝大多数 SWN 患者都表现出顽固性、衰弱的症状。 慢性疼痛，严重程度足以导致永久性残疾 SWN 疼痛的病因尚不清楚。 SWN 和相关疼痛的新疗法的开发极其缓慢且效率低下。 对于 SWN 仅限于侵入性手术，该手术具有进一步神经损伤的显着风险，目前尚无药物。 FDA 批准用于阻止 SWN 肿瘤生长或减轻 SWN 相关疼痛。 SWN研究的挑战是缺乏临床相关模型，我们成功建立了源自患者的模型 SWN 细胞系，并在原位坐骨神经和脊柱小鼠模型中培养它们，这些模型可复制肿瘤 在初步研究中，使用这些新型患者来源的异种移植模型（PDX），我们发现： i) 周围神经中生长的肿瘤病变导致巨噬细胞涌入背根神经节 (DRG)，ii) SWN 肿瘤衍生的高迁移率组 Box1 (HMGB1)，一种关键的炎症引发剂和 放大器，调节关键巨噬细胞 C-C 基序趋化因子配体 2 (CCL2) 的神经元表达 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 中和抗体可显着降低疼痛反应，但对疼痛反应效果甚微 原位 SWN PDX 模型中的肿瘤生长，v) 抗 IL-6 治疗激活 EGFR 信号传导， 基于这些令人兴奋的发现，我们认为：i) SWN 衍生的。 HMGB1 刺激感觉神经元表达 CCL2，从而将巨噬细胞招募到 DRG，ii) 巨噬细胞通过过量产生 IL-6 引起疼痛反应，并且 iii) 联合 IL-6 和 EGFR 阻断可以 在目标 1 中，使用原位 SWN PDX 同时减轻疼痛并抑制肿瘤生长。 模型中，我们将进行功能丧失实验来评估肿瘤来源的 HMGB1 在 然后，我们将研究神经元（CCL2）-巨噬细胞（CCR2）轴是否调节。 利用骨髓来源的过继转移，在巨噬细胞募集和疼痛反应中至关重要 在目标 2 中，我们将使用基因沉默和药物抑制来评估来自 Ccr2-/- 小鼠的巨噬细胞。 肿瘤源性与巨噬细胞源性 IL-6 信号传导对原位 SWN 疼痛反应的贡献 PDX模型；此外，我们将确定IL-6中和抗体在减轻疼痛反应方面的功效。 在目标 3 中，我们将检验联合 IL-6 和 EGFR 阻断可有效延缓肿瘤发生的假设 原位 SWN PDX 模型中的生长和减少疼痛反应 影响：如果成功，本研究将 i) 为肿瘤 (HMGB1)-神经元 (CCL2)- 的作用提供关键的细胞和分子机制见解 巨噬细胞 (IL-6) 串扰导致 SWN 疼痛，并且 ii) 使用 FDA 批准的 IL-6 和 EGFR 抑制剂 同时减轻 SWN 的疼痛并控制肿瘤生长。