Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Int J Radiat Oncol Biol Phys. 2021 Dec 1;111(5):e63-e74. doi: 10.1016/j.ijrobp.2021.07.1694. Epub 2021 Jul 31.
The development of molecular targeted drugs with radiation and chemotherapy is critically important for improving the outcomes of patients with hard-to-treat, potentially curable cancers. However, too many preclinical studies have not translated into successful radiation oncology trials. Major contributing factors to this insufficiency include poor reproducibility of preclinical data, inadequate preclinical modeling of intertumoral genomic heterogeneity that influences treatment sensitivity in the clinic, and a reliance on tumor growth delay instead of local control (TCD50) endpoints. There exists an urgent need to overcome these barriers to facilitate successful clinical translation of targeted radiosensitizers. To this end, we have used 3-dimensional (3D) cell culture assays to better model tumor behavior in vivo. Examples of successful prediction of in vivo effects with these 3D assays include radiosensitization of head and neck cancers by inhibiting epidermal growth factor receptor or focal adhesion kinase signaling, and radioresistance associated with oncogenic mutation of KRAS. To address the issue of tumor heterogeneity, we leveraged institutional resources that allow high-throughput 3D screening of radiation combinations with small-molecule inhibitors across genomically characterized cell lines from lung, head and neck, and pancreatic cancers. This high-throughput screen is expected to uncover genomic biomarkers that will inform the successful clinical translation of targeted agents from the National Cancer Institute Cancer Therapy Evaluation Program portfolio and other sources. Screening "hits" need to be subjected to refinement studies that include clonogenic assays, addition of disease-specific chemotherapeutics, target/biomarker validation, and integration of patient-derived tumor models. The chemoradiosensitizing activities of the most promising drugs should be confirmed in TCD50 assays in xenograft models with or without relevant biomarker and using clinically relevant radiation fractionation. We predict that appropriately validated and biomarker-directed targeted therapies will have a higher likelihood than past efforts of being successfully incorporated into the standard management of hard-to-treat tumors.
开发与放化疗相结合的分子靶向药物对于改善治疗难度大、有治愈可能的癌症患者的预后至关重要。然而，太多的临床前研究未能转化为成功的放射肿瘤学试验。导致这种不足的主要因素包括临床前数据的可重复性差、未能充分模拟影响临床治疗敏感性的肿瘤间基因组异质性的临床前模型，以及对肿瘤生长延迟而不是局部控制 (TCD50) 终点的依赖。迫切需要克服这些障碍，以促进靶向增敏剂的成功临床转化。为此，我们使用 3 维（3D）细胞培养测定来更好地模拟体内肿瘤行为。这些 3D 测定成功预测体内效应的例子包括通过抑制表皮生长因子受体或黏着斑激酶信号转导来增敏头颈部癌症，以及与 KRAS 致癌突变相关的放射抗性。为了解决肿瘤异质性问题，我们利用机构资源，能够在高通量 3D 筛选中，对来自肺癌、头颈部癌和胰腺癌的基因组特征化细胞系中的辐射组合与小分子抑制剂进行筛选。这种高通量筛选有望发现基因组生物标志物，为成功转化来自国家癌症研究所癌症治疗评估计划组合和其他来源的靶向药物提供信息。需要对筛选“命中”进行精细研究，包括集落形成测定、添加特定疾病的化疗药物、目标/生物标志物验证以及整合患者来源的肿瘤模型。最有前途的药物的化学放射增敏活性应在含有或不含有相关生物标志物的异种移植模型中通过 TCD50 测定和使用临床相关的辐射分割进行确认。我们预测，经过适当验证和基于生物标志物的靶向治疗比过去的努力更有可能成功纳入治疗难度大的肿瘤的标准治疗方案。
