Department of Radiation Oncology, UT MD Anderson Cancer Center, Houston, Texas; Graduate School of Biological Sciences, UT MD Anderson Cancer Center, Houston, Texas.
Department of Radiation Oncology, UT MD Anderson Cancer Center, Houston, Texas.
Int J Radiat Oncol Biol Phys. 2021 Dec 1;111(5):e27-e37. doi: 10.1016/j.ijrobp.2021.07.1712. Epub 2021 Aug 2.
The combination of cytotoxic chemotherapy with radiation therapy (CRT) has resulted in significant improvements in clinical outcomes for patients with many locally advanced unresectable cancers. Only a small proportion of patients achieve pathologic complete responses to CRT; combination of CRT with targeted agents offers the promise of further improving treatment responses. However, numerous clinical trials have failed to show an improvement in clinical outcomes with the addition of targeted agents. To increase the accessibility of our screening method and accelerate the pace at which novel combinations with CRT are identified and incorporated into standard practices for treatments, we report details on screening method optimization, data generation, and downstream data analysis.
In part, the gap in translation to large, expensive, and ultimately unsuccessful clinical trials reflects the shortcomings of inconsistently designed, executed, and reported preclinical data on which these studies are based. In an effort to standardize the selection of agents for future clinical testing, we have designed, optimized and validated a high throughput, high content, clonogenic assay platform for step-wise progression of preclinical studies from in vitro to in vivo in non-small cell lung cancer and pancreatic ductal adenocarcinoma.
This highly stable in vitro method was standardized for identification of the most promising CTEP drugs that could best be combined with CRT from among as screen of multiple agents tested in an unbiased manner using 96-well plates. The methodology lends itself to seamless testing of multiple agents in a similar fashion allowing cross-comparisons, evaluation of CRT, or radiation therapy alone, and testing multiple concentrations of test agents sequenced at different times before and after radiation. The method identified Trametinib as a strong CRT sensitizer in KRAS-mutant non-small cell lung cancer and pancreatic ductal adenocarcinoma cell lines. This platform has enabled the screening and identification of several chemoradiation sensitizers.
High throughput, high content clonogenic drug screening assay allows for the rapid identification of targets and agents to be translated to the clinic to help improve the effectiveness of current standard of care CRT in various solid tumors.
细胞毒性化疗联合放射治疗（CRT）显著改善了许多局部晚期不可切除癌症患者的临床结局。只有一小部分患者对 CRT 达到病理完全缓解；将 CRT 与靶向药物联合使用有望进一步提高治疗反应。然而，许多临床试验未能显示添加靶向药物可改善临床结局。为了增加我们的筛选方法的可及性，并加速将与 CRT 联合的新组合识别出来并纳入标准治疗实践，我们报告了有关筛选方法优化、数据生成和下游数据分析的详细信息。
部分原因是，向大型、昂贵且最终失败的临床试验的转化存在差距，这反映了基于这些研究的临床前数据在设计、执行和报告方面存在不一致的缺陷。为了标准化未来临床测试中药物的选择，我们设计、优化并验证了一种高通量、高内涵、克隆形成测定平台，用于逐步推进非小细胞肺癌和胰腺导管腺癌的临床前研究，从体外到体内。
这种高度稳定的体外方法已标准化，用于识别最有前途的 CTEP 药物，这些药物可以在不偏不倚的情况下，使用 96 孔板以最佳方式与 CRT 联合使用，筛选出经过测试的多种药物。该方法适用于以类似方式对多种药物进行无缝测试，从而允许进行交叉比较、评估 CRT 或单独放射治疗，以及在放射治疗前后的不同时间测试多种测试药物浓度。该方法确定 Trametinib 是 KRAS 突变型非小细胞肺癌和胰腺导管腺癌细胞系中强有力的 CRT 增敏剂。该平台已能够筛选和鉴定几种化学放射增敏剂。
高通量、高内涵克隆形成药物筛选测定法可快速鉴定靶标和药物，将其转化为临床，有助于提高各种实体瘤中当前标准 CRT 的疗效。
