Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma.
Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma.
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DOI：
10.20517/cdr.2021.112
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Houghton PJ
中科院分区：
文献类型：
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作者：
Ghilu S;Morton CL;Vaseva AV;Zheng S;Kurmasheva RT;Houghton PJ
目的：尽管采用了积极的多药治疗方案，但转移性横纹肌肉瘤（RMS）患者预后较差。在最近的一项高风险试验（ARST0431）中，25%的患者在接受治疗的第一年内失败，80%的患者在24个月内肿瘤进展。然而，肿瘤耐药性的机制基本上是未知的。在这里，我们探索使用临床前模型来开发对ARST0431中使用的复杂化疗方案的耐药性。方法：采用单小鼠试验（SMT）方法评价34个RMS异种移植模型对长春新碱、放线菌素D、环磷酰胺（VAC）一个周期治疗的敏感性。通过卡尺测量确定肿瘤反应，肿瘤回归和无事件生存（EFS）作为评估终点。再生长的治疗肿瘤被移植到受体小鼠中，重复治疗，直到肿瘤在治疗期间进展（即产生耐药性）。移植时，保存肿瘤组织进行生化和组学分析。结果：测定了34个RMS模型对VAC的敏感性。EFS从3周到20周不等。肿瘤模型被分类为对VAC治疗具有内在抗性、中等敏感性和高敏感性。在2-5个治疗周期后，多个模型出现了对VAC的耐药性；然而，也有在治疗3个周期后敏感性保持不变的例子。结论：SMT方法可以在体内评估大量RMS模型的药物敏感性和耐药性的发展。因此，它提供了一个在“种群”水平上评估体内耐药机制的平台，模拟体内导致临床耐药的条件。这些抗vaca模型代表了模拟临床前2期人群的“高风险”肿瘤，对于识别抗vaca耐药疾病的新药物具有价值。
Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431. Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis. Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment. Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a “population” level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent “high-risk” tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.