GlycoMira Therapeutics, Salt Lake City, Utah, United States of America.
Biomodels, Waltham, Massachusetts, United States of America.
PLoS One. 2021 Mar 26;16(3):e0249343. doi: 10.1371/journal.pone.0249343. eCollection 2021.
Oral mucositis (OM) is a common, painful side effect of radiation therapy used for the treatment of head and neck cancer (HNC). Activation of the innate immune system upon irradiation has been identified as a key precipitating event of OM. To better understand OM's pathogenesis, we studied pattern recognition receptors (PRRs) and their downstream pro-inflammatory cytokines in a mouse model of radiation-induced OM. We also tested therapeutic efficacy of GM-1111 that targets innate immune system to reduce radiation-induced OM.
The pathogenesis of OM was studied in a single X-ray induced mouse model. The severity of OM was measured by visual and microscopical examinations. The irradiation-induced changes of PRRs and their downstream effector cytokine gene expression levels were determined. The efficacy of GM-1111 to reduce OM was tested in single and fractionated irradiation mouse models. The impact of the drug on tumor response to radiation therapy was also tested in a mouse model of human HNC.
Radiation-induced tissue ulcerations were radiation-dosage and -time dependent. The lesions showed selective increases in PRR and pro-inflammatory cytokine gene expression levels. Once daily administration of GM-1111 (≥30 mg/kg, s.c.) significantly reduced the severity and the incidence of OM. The drug had little effect on PRRs but significantly inhibited downstream pro-inflammatory cytokine genes. GM-1111 did not interfere radiation therapy to induce HNC SCC-25 tumor regression. Instead, we observed significant drug-induced tumor regression.
Radiation induces tissue damages. The increased expression levels of PRRs and their downstream pro-inflammatory cytokine genes in the damaged tissues suggest their important contribution to the pathogenesis of OM. Drug GM-1111 that targets these innate immune molecules may be a potential drug candidate as an intervention for OM.
口腔黏膜炎（OM）是头颈部癌症（HNC）放射治疗的常见、疼痛副作用。照射后固有免疫系统的激活已被确定为 OM 的一个关键引发事件。为了更好地了解 OM 的发病机制，我们在放射诱导的 OM 小鼠模型中研究了模式识别受体（PRR）及其下游促炎细胞因子。我们还测试了靶向固有免疫系统以减少放射诱导的 OM 的 GM-1111 的治疗效果。
在单次 X 射线诱导的小鼠模型中研究 OM 的发病机制。通过视觉和显微镜检查测量 OM 的严重程度。确定 PRR 及其下游效应细胞因子基因表达水平的照射诱导变化。在单次和分次照射小鼠模型中测试 GM-1111 降低 OM 的效果。还在 HNC 的人类模型中测试了该药物对肿瘤对放射治疗反应的影响。
辐射诱导的组织溃疡与辐射剂量和时间有关。病变显示 PRR 和促炎细胞因子基因表达水平选择性增加。每天一次给予 GM-1111（≥30mg/kg，sc）可显著减轻 OM 的严重程度和发生率。该药物对 PRR 影响不大，但明显抑制下游促炎细胞因子基因。GM-1111 不干扰放射治疗诱导 HNC SCC-25 肿瘤消退。相反，我们观察到药物诱导的肿瘤明显消退。
辐射会引起组织损伤。受损组织中 PRR 及其下游促炎细胞因子基因的表达水平增加表明它们对头颈部癌症放射治疗中 OM 的发病机制有重要贡献。针对这些固有免疫分子的药物 GM-1111 可能是一种有潜力的干预 OM 的候选药物。
