Relating Drugs to Genotypes to Transform Precision Cancer Therapeutics with Tuba-seq - a Novel, Highly Scalable and Quantitative Preclinical Experimental Oncology Platform

利用 Tuba-seq 将药物与基因型联系起来，以改变精准癌症治疗——一种新颖、高度可扩展的定量临床前实验肿瘤学平台

• 批准号: 10256762
• 负责人: Ian Paul Winters
• 金额: $ 86.51万
• 依托单位: D2G ONCOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256762
• 关键词: Animal Model; Animals; Antineoplastic Agents; Bar Codes; Bioinformatics; CRISPR/Cas technology; Cancer Etiology; Cancer Patient; Cells; Clinical; Clinical Trials; Custom; DNA; DNA Sequence Alteration; Data; Drug Interactions; Engineering; Ensure; Experimental Models; Fill-It; Future; Genes; Genetically Engineered Mouse; Genome; Genotype; Goals; Human; Immunocompetent; Immunooncology; Immunotherapy; Individual; Inherited; Lead; Lentivirus Vector; Letters; Licensing; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; Modeling; Mus; Oncogenic; Oncology; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacologic Substance; Phase; Protocols documentation; Publications; Reporting; Research Personnel; Services; Small Business Innovation Research Grant; Source; Specific qualifier value; Techniques; Technology; Therapeutic; Time; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Universities; Validation; Variant; Work; cancer cell; cancer therapy; cohort; design; drug candidate; drug discovery; experimental study; human cancer mouse model; improved; in vivo; innovation; interest; lentiviral-mediated; neoplastic cell; novel; oncology program; patient response; personalized cancer therapy; personalized medicine; pre-clinical; response; somatic cell gene editing; success; treatment effect; tumor; tumor barcoding and sequencing

PROJECT SUMMARY D2G Oncology, Inc. proposes to develop a novel preclinical experimental platform that will effectively relate cancer drugs to genotypes (“D2G”) to predict pharmacogenomic interactions. D2G Oncology's innovative approach dramatically improves on established autochthonous mouse models of human cancer. These proven models allow controlled genomic alterations to initiate tumors in vivo in an appropriate immune-competent microenvironment and faithfully recapitulate progression of human cancer. D2G's innovative methods for the first time enable these animal models to become truly scalable and rigorously quantitative, and hence prac- tical to support drug discovery. D2G's approach can efficiently interrogate a large matrix of tumor genotypes to predict differential patient responses to therapies. Pharmaceutical companies are eager to obtain this infor- mation. D2G will significantly advance the state of the art in precision cancer therapy by helping pharma to rationally select candidate compounds to advance and better match them to patients. D2G's oncology platform will increase the success rate of clinical trials and lead to more effective personalized cancer treatments. The key innovation is a novel tumor barcoding and sequencing (Tuba-seq) pipeline. Every clonal tumor is uniquely barcoded, so the identity and number of cancer cells in each tumor can be readily quantified from bulk tumor-bearing tissues. Combined with lentiviral-mediated CRISPR/Cas9 somatic genome editing, tumor barcoding allows many predefined tumor genotypes to be generated all at once in individual animals and tracked separately. Tuba-seq enables many tens of experiments (which would each ordinarily require separate cohorts of mice) to be multiplexed into a single mouse. Compared with conventional genetically engineered mouse models, this approach enormously enhances scalability, introduces rigorous quantification, and reduces sources of variation. The overall goal of the proposed Direct Phase 2 SBIR project is to transform the Tuba-seq pipeline into a robust platform that can be marketed as a commercial service to pharmaceutical companies. Specific aims are to (1) expand the panel of tumor suppressor genes that the platform interrogates and carefully calibrate their effect sizes and (2) rigorously validate the ability of the platform to resolve small but clinically meaningful differences in tumor suppressor gene-drug effect sizes with high statistical confidence, relying only on small cohorts of ani- mals. D2G will create the first practical and scalable preclinical experimental modeling approach that can assess how candidate drugs interact with diverse, precisely-engineered cancer genotypes to predict differential patient responses to therapy.

项目摘要 D2G Oncology，Inc.建议开发一种新的临床前实验平台， 癌症药物与基因型（“D2 G”）的相互作用，以预测药物基因组学相互作用。D2 G Oncology的创新 这种方法极大地改善了已建立的人类癌症本地小鼠模型。这些经过验证 模型允许受控的基因组改变，以在适当的免疫活性细胞中在体内引发肿瘤， 微环境和忠实地重演人类癌症的进展。D2 G的创新方法 第一次使这些动物模型成为真正的可扩展和严格的定量，因此实践， 支持药物发现。D2 G的方法可以有效地询问大量的肿瘤基因型矩阵， 预测患者对治疗的不同反应。制药公司渴望获得这一信息- mation。D2 G将通过帮助制药公司， 合理选择候选化合物，以推进并更好地将其与患者相匹配。D2 G的肿瘤学平台 将提高临床试验的成功率，并带来更有效的个性化癌症治疗。 关键的创新是一种新的肿瘤条形码和测序（Tuba-seq）管道。每个克隆性肿瘤 独特的条形码，因此每个肿瘤中的癌细胞的身份和数量可以容易地从 大块的肿瘤组织结合慢病毒介导的CRISPR/Cas9体细胞基因组编辑， 条形码化允许在个体动物中一次产生许多预定义的肿瘤基因型， 分开追踪。Tuba-seq可以进行数十个实验（每个实验通常需要单独的 小鼠群）被多路复用到单个小鼠中。与传统的基因工程相比 小鼠模型，这种方法极大地增强了可扩展性，引入了严格的量化，并减少了 变异的来源。 拟议的直接第2阶段SBIR项目的总体目标是将Tuba-seq管道转变为一个强大的 该平台可以作为商业服务向制药公司销售。具体目标是（1） 扩展平台所询问的肿瘤抑制基因组，并仔细校准它们的作用 尺寸和（2）严格验证平台解决微小但有临床意义差异的能力 在具有高统计置信度的肿瘤抑制基因药物效应量中，仅依赖于小的ANI队列， 马尔斯 D2 G将创建第一个实用且可扩展的临床前实验建模方法， 候选药物与不同的，精确工程化的癌症基因型相互作用，以预测不同的患者 对治疗的反应。