Screening and Validation of Molecular Targeted Radiosensitizers.
Screening and Validation of Molecular Targeted Radiosensitizers.
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DOI：
10.1016/j.ijrobp.2021.07.1694
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Krause M
中科院分区：
文献类型：
--
作者：
Willers H;Pan X;Borgeaud N;Korovina I;Koi L;Egan R;Greninger P;Rosenkranz A;Kung J;Liss AS;Parsels LA;Morgan MA;Lawrence TS;Lin SH;Hong TS;Yeap BY;Wirth LJ;Hata AN;Ott CJ;Benes CH;Baumann M;Krause M
分子靶向药物与放疗和化疗的发展对于改善难以治疗的、可能治愈的癌症患者的预后至关重要。然而，太多的临床前研究尚未转化为成功的放射肿瘤学试验。造成这一不足的主要因素包括临床前数据的重现性差，影响临床治疗敏感性的肿瘤间基因组异质性的临床前建模不足，以及依赖肿瘤生长延迟而不是局部对照（TCD 50）终点。迫切需要克服这些障碍，以促进靶向放射增敏剂的成功临床转化。为此，我们采用了3D细胞培养试验来更好地模拟体内肿瘤行为。用这些3D测定法成功预测体内效应的实例包括通过抑制表皮生长因子受体或粘着斑激酶信号传导对头颈癌的放射增敏，以及与KRAS致癌突变相关的放射抗性。为了解决肿瘤异质性的问题，我们利用机构资源，允许在肺癌、头颈癌和胰腺癌的基因组特征细胞系中高通量3D筛选放射组合与小分子抑制剂。这种高通量筛选有望发现基因组生物标志物，这些生物标志物将为NCI CTEP产品组合和其他来源的靶向药物的成功临床翻译提供信息。筛选“命中”需要进行细化研究，包括克隆形成测定、添加疾病特异性化疗剂、靶标/生物标志物验证和患者来源的肿瘤模型的整合。最有前途的药物的化学放射增敏活性应在具有/不具有相关生物标志物的异种移植模型中的TCD 50测定中确认，并利用临床相关的放射分级。我们预测，经过适当验证和生物标志物导向的靶向治疗将比过去的努力更有可能成功地纳入难以治疗的肿瘤的标准管理。
The development of molecular targeted drugs with radiation and chemotherapy are 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 inter-tumoral 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 employed 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 NCI CTEP 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/without relevant biomarker and utilizing clinically relevant radiation fractionation. We predict that appropriately validated and biomarker-directed targeted therapies will have a higher likelihood than past efforts to be successfully incorporated into the standard management of hard-to-treat tumors.
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影响因子：
2.6
作者：
Dai, Xiao-Fang;Ding, Jie;Wu, Gang
通讯作者：
Wu, Gang
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
DOI：
10.1073/pnas.1411848112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Faber, Anthony C.;Farago, Anna F.;Engelman, Jeffrey A.
通讯作者：
Engelman, Jeffrey A.
影响因子：
11.5
作者：
Ahmad, Saif S.;Crittenden, Marka R.;Sharma, Ricky A.
通讯作者：
Sharma, Ricky A.