High-Throughput Screening and Validation of Molecular Targeted Chemoradiosensitizers

分子靶向放化疗增敏剂的高通量筛选和验证

• 批准号: 10433852
• 负责人: Aaron N Hata
• 金额: $ 55.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433852
• 关键词: 3-Dimensional; Animal Testing; Antineoplastic Agents; Biological Assay; Biological Markers; Budgets; Cancer Burden; Cancer Center; Cancer Therapy Evaluation Program; Cancer cell line; Cell Line; Cells; Cessation of life; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Collection; Combined Modality Therapy; Community Clinical Oncology Program; Coupled; Data; Disease; Drug Combinations; Drug Targeting; Environment; Evaluation; Exposure to; Extracellular Matrix; Fractionation; General Hospitals; Genomics; Genotype; German population; Goals; Growth; Head Cancer; Heterogeneity; In Vitro; Institutes; Inter-tumoral heterogeneity; KRAS2 gene; Knowledge; Laminin; Lead; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of lung; Massachusetts; Measures; Mission; Modeling; Molecular Target; Mus; Mutate; NCI Center for Cancer Research; Neck Cancer; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pre-Clinical Model; Preclinical Testing; Probability; Process; Property; Public Health; Radiation; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Radiobiology; Radiosensitization; Recommendation; Reproducibility; Research; Research Personnel; Resources; Robotics; Solid Neoplasm; Testing; Therapy trial; Translating; Trust; United States; United States National Institutes of Health; Validation; Xenograft Model; Xenograft procedure; anticancer research; base; biomarker validation; cancer cell; candidate marker; chemoradiation; chemotherapy; clinical development; clinical translation; clinically relevant; cost; drug sensitivity; drug testing; expectation; experimental study; fractionated radiation; genomic biomarker; genomic variation; high throughput screening; improved outcome; in vivo; in vivo Model; inhibitor; irradiation; molecular drug target; oncology trial; pre-clinical; preclinical development; radiation effect; response; screening; standard of care; success; targeted agent; targeted biomarker; targeted treatment; tumor; tumor growth; tumor xenograft; validation studies

PROJECT SUMMARY Preclinical and clinical development of molecular targeted drugs with radiation therapy (RT) and chemotherapy are critically important for improving the outcomes of patients with hard-to-treat cancers. However, a huge body of preclinical drug/RT studies has not translated into an adequate number of successful radiation oncology trials. Major contributing factors include poor reproducibility of preclinical data, insufficient preclinical modeling of inter-tumoral genomic heterogeneity that influences treatment sensitivity in the clinic, and reliance on tumor growth delay instead of local tumor control (TCD50) endpoints. There exists an urgent need to overcome these barriers to successful clinical translation of targeted chemoradiosensitizers. We propose to establish an integrated in-vitro/in-vivo pipeline for chemoradiosensitizing targeted drugs that are biomarker-correlated and appropriately validated, so that subsequent clinical drug/RT trials in patients with hard-to-treat cancers will have a substantially higher probability of success than in the past. To achieve this, we propose 3 Specific Aims. First, by leveraging the unique expertise and resources that the Genomics of Drug Sensitivity in Cancer project (Massachusetts General Hospital & UK Wellcome Trust Sanger Institute) and the German Cancer Research Center/Cancer Consortium (DKFZ/DKTK) offer, we will conduct a robotic high-throughput screen of cancer cell lines grown in an extracellular-matrix (ECM) based 3D format to better mimic in-vivo growth conditions. We propose to screen about half of the current CTEP portfolio (30 drugs) combined with fractionated irradiation across an initial panel of 100 annotated cell lines selected to represent clinically relevant inter-tumoral genomic variation. Second, we propose a systematic and stepwise validation/refinement process to nominate CTEP drugs that have the highest likelihood to succeed in animal testing. This will include 3D colony formation assays, addition of disease-specific chemotherapy, confirmation of pharmacodynamic responses, target/biomarker validation, and integration of patient-derived cell lines and xenografts. Third, we will evaluate the chemoradiosensitizing effects of the most promising CTEP drugs in-vivo by relying on TCD50 assays in mouse xenograft models with/without biomarker and utilizing clinically relevant RT fractionation (30 fractions/6 weeks). These experiments again will leverage special DKFZ/DKTK capability. The proposed studies are directly relevant to the objectives of the underlying FOA, as we will, in close collaboration with investigators within and outside the consortium, accelerate the pace at which targeted chemoradiation treatments with greater efficacy are identified. This undertaking will be greatly facilitated by the integration of a foreign project component where DKFZ/DKTK investigators contribute special expertise in 3D ECM and TCD50 assays at low budget cost, which will directly and disproportionally benefit the NCI and the radiation oncology community in the United States. By integrating extensive expertise in pharmacogenomics and radiation biology, the inter-disciplinary investigator team is uniquely poised to help transform the preclinical discovery process for chemoradiosensitizing targeted drugs with accompanying biomarkers.

项目概要 放射治疗（RT）和分子靶向药物的临床前和临床开发 化疗对于改善难治性癌症患者的预后至关重要。 然而，大量的临床前药物/RT 研究尚未转化为足够数量的成功案例 放射肿瘤学试验。主要影响因素包括临床前数据的重复性差、不足 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， 并依赖肿瘤生长延迟而不是局部肿瘤控制（TCD50）终点。存在紧急情况 需要克服这些障碍才能成功地将靶向放化疗增敏剂临床转化。我们 提议建立放化疗增敏靶向药物的综合体外/体内管道 生物标志物相关并经过适当验证，以便随后在患有以下疾病的患者中进行临床药物/RT试验 难以治疗的癌症的成功概率将比过去高得多。为了实现这一目标， 我们提出 3 个具体目标。首先，通过利用基因组学的独特专业知识和资源， 癌症药物敏感性项目（麻省总医院和英国威康信托桑格研究所） 和德国癌症研究中心/癌症联盟 (DKFZ/DKTK) 的提议，我们将进行机器人 对基于细胞外基质 (ECM) 的 3D 格式生长的癌细胞系进行高通量筛选，以更好地 模拟体内生长条件。我们建议筛选当前 CTEP 产品组合中约一半（30 种药物） 结合对初始面板的分次照射，该面板由 100 个选定代表的带注释的细胞系组成 临床相关的肿瘤间基因组变异。其次，我们提出了系统化、分步实施的方案。 提名最有可能在动物身上取得成功的 CTEP 药物的验证/细化过程 测试。这将包括 3D 集落​​形成测定、添加疾病特异性化疗、确认 药效学反应、靶点/生物标志物验证以及患者来源的细胞系的整合和 异种移植物。第三，我们将评估最有前途的CTEP药物的体内放化疗增敏作用 依赖于有/无生物标志物的小鼠异种移植模型中的 TCD50 测定并利用临床相关的 RT 分段（30 次分段/6 周）。这些实验将再次利用特殊的 DKFZ/DKTK 功能。 拟议的研究与基础 FOA 的目标直接相关，我们将密切关注 与联盟内外的调查人员合作，加快目标确定的步伐 已确定具有更佳疗效的放化疗治疗。这项工作将得到极大的促进 整合外国项目组件，其中 DKFZ/DKTK 研究人员贡献 3D 方面的特殊专业知识 ECM 和 TCD50 检测的预算成本较低，这将直接且不成比例地使 NCI 和 美国放射肿瘤学界。通过整合药物基因组学方面的广泛专业知识 和放射生物学，跨学科研究团队独特地准备帮助改变临床前 具有伴随生物标志物的放化疗增敏靶向药物的发现过程。

项目成果

Sample-size calculation for preclinical dose-response experiments using heterogeneous tumour models.

• DOI: 10.1016/j.radonc.2021.02.032
• 发表时间: 2021-05
• 期刊: RADIOTHERAPY AND ONCOLOGY
• 影响因子: 5.7
• 作者: Ciecior, Willy;Ebert, Nadja;Borgeaud, Nathalie;Thames, Howard D.;Baumann, Michael;Krause, Mechthild;Loeck, Steffen
• 通讯作者: Loeck, Steffen

Targeting the DNA replication stress phenotype of KRAS mutant cancer cells.

• DOI: 10.1038/s41598-021-83142-y
• 发表时间: 2021-02-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Al Zubaidi T;Gehrisch OHF;Genois MM;Liu Q;Lu S;Kung J;Xie Y;Schuemann J;Lu HM;Hata AN;Zou L;Borgmann K;Willers H
• 通讯作者: Willers H

Alginate-based 3D cancer cell culture for therapeutic response modeling.

• DOI: 10.1016/j.xpro.2021.100391
• 发表时间: 2021-06-18
• 期刊: STAR protocols
• 作者: Davoudi F;Ghorbanpoor S;Yoda S;Pan X;Crowther GS;Yin X;Murchie E;Hata AN;Willers H;Benes CH
• 通讯作者: Benes CH