Harnessing treatment-induced tumor evolution and collateral sensitivities using a human rectal cancer co-clinical platform

使用人类直肠癌联合临床平台利用治疗诱导的肿瘤进化和附带敏感性

• 批准号: 10524569
• 负责人: Christine Elissa Eyler
• 金额: $ 24.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524569
• 关键词: Address; Architecture; Benchmarking; CRISPR/Cas technology; Cancer Model; Cancer Patient; Cells; Chemotherapy and/or radiation; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Colostomy Procedure; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Disease; Drug Screening; Effectiveness; Epigenetic Process; Evaluation; Evolution; Excision; Experimental Models; Foundations; Genetic; Genomics; Genotype; Goals; Human; Implant; In complete remission; Infrastructure; Instruction; KRAS2 gene; Laboratories; Light; Malignant Neoplasms; Mentors; Methods; Modeling; Mutation; Neoadjuvant Therapy; Operative Surgical Procedures; Organoids; Pathologic; Patients; Phenotype; Radiation therapy; Rectal Cancer; Rectal Neoplasms; Rectum; Research; Resistance; Sampling; Specimen; Structure; TP53 gene; Techniques; Thick; Time; Training; Treatment outcome; Tumor Volume; Tumor-Derived; Variant; Xenograft Model; advanced disease; base; career development; chemoradiation; chemotherapy; design; drug sensitivity; epigenomics; experience; genome-wide; high-throughput drug screening; improved; innovation; knowledge base; lymph nodes; mutant; neoplastic cell; non-genetic; novel; patient derived xenograft model; patient subsets; radioresistant; rectal; resistance mechanism; response; screening; single-cell RNA sequencing; standard care; subclonal heterogeneity; success; targeted treatment; therapeutic target; therapy resistant; treatment strategy; trend; tumor

PROJECT SUMMARY/ABSTRACT Locally advanced rectal cancer, defined by spread to lymph nodes or extension through the full rectal wall thickness, is diagnosed in over 15,000 US patients yearly. Standard treatment for locally advanced rectal cancer in the US involves chemotherapy and radiation therapy (chemoradiation, CRT) prior to surgical removal of the entire rectum. Patients may experience undesirable post-surgical consequences such as permanent colostomy or altered anorectal function. In light of this, much ongoing research focuses on strategies to avoid surgical intervention in the subset of patients who might be cured with CRT alone. At the time of surgery, 10- 30% of tumors are eradicated by CRT (i.e., they demonstrate a pathologic complete response) while other tumors show little to no response. This variability in response is incompletely understood, but likely relates to the fact that one tumor may contain numerous different tumor cell subpopulations, all with different genotypes and epigenetic (or non-genetic) features. These diverse subpopulations and variable genetic/epigenetic features can interact, resulting in a dynamic and evolving tumor cell network that is poorly understood. In an increasing number of cancers, there is evidence supporting the emergence of treatment-induced evolutionary “traps,” or “collateral sensitivities”, where resistance to one therapy results in sensitivity to another therapy. Whether this occurs in rectal cancer, and how to leverage it into treatment strategies, is unclear. To address these questions, it is crucial to select a representative experimental model. Thus, the current proposal leverages an already-established co-clinical pipeline from which patient derived tumor samples are used to generate paired, patient-specific organoid and xenograft models. Two broad analytic approaches will be undertaken to identify trends in CRT-induced tumor evolution and elucidate potential synergistic approaches to improve CRT response. Specific Aim 1 will dissect CRT-induced changes using genomic, epigenomic, and single cell profiling techniques, including an advanced method combining single cell RNA-seq with lineage tracing. Specific Aim 2 employs an innovative iterative paired CRISPR/high throughput drug screen approach to identify evolving collateral sensitivities in CRT-treated rectal cancer. To validate the findings in both Aims, advanced patient-derived rectal cancer organoid and xenograft models will be utilized. Research, scientific instruction, and career development will be supported by an expert panel of mentors and collaborators and a structured training plan. Successful completion of both Aims will be promoted by the expertise and existing screening and genomic infrastructure in the co-mentors’ laboratories and leverages a unique co-clinical platform already established by close institutional collaborators. This research will establish a patient-derived platform for interrogating CRT-induced tumor evolution, establishing a scientific niche to facilitate success during the transition to scientific independence.

项目摘要/摘要 局部晚期直肠癌，定义为扩散至淋巴结或扩展至整个直肠壁 在美国，每年有超过15，000名患者被诊断出患有这种疾病。局部晚期直肠癌的标准治疗 在美国，癌症在手术切除之前涉及化学疗法和放射疗法（化学放射疗法，CRT 整个直肠。患者可能会出现不良的术后后果，如永久性 结肠造口术或肛门直肠功能改变。有鉴于此，许多正在进行的研究侧重于避免 在可能仅用CRT治愈的患者亚组中进行外科干预。手术时，10- 30%的肿瘤被CRT根除（即，它们表现出病理学完全反应），而其他 肿瘤几乎没有反应。这种反应的变异性尚不完全清楚，但可能与以下因素有关： 事实上，一个肿瘤可能含有许多不同的肿瘤细胞亚群，都具有不同的基因型 和表观遗传（或非遗传）特征。这些不同的亚群和可变的遗传/表观遗传 特征可以相互作用，导致动态和进化的肿瘤细胞网络，这是知之甚少。中 越来越多的癌症，有证据支持治疗诱导的进化的出现， “陷阱”或“附带敏感性”，其中对一种疗法的抗性导致对另一种疗法的敏感性。 这种情况是否发生在直肠癌中，以及如何将其用于治疗策略，目前尚不清楚。解决 这些问题，选择一个有代表性的实验模型是至关重要的。因此，目前的提案 利用已经建立的合作临床管道，患者来源的肿瘤样本用于 产生成对的、患者特异性的类器官和异种移植物模型。两种广泛的分析方法将是 研究旨在确定CRT诱导的肿瘤演变趋势，并阐明潜在的协同方法， 改善CRT响应。具体目标1将使用基因组、表观基因组和 单细胞分析技术，包括将单细胞RNA-seq与谱系相结合的先进方法 追踪Specific Aim 2采用创新的迭代配对CRISPR/高通量药物筛选方法 以确定CRT治疗直肠癌中不断变化的侧支敏感性。为了验证这两个目标的结果， 将使用晚期患者来源的直肠癌类器官和异种移植物模型。研究、科学 教学和职业发展将得到一个由导师和合作者组成的专家小组的支持， 结构化培训计划。这两个目标的成功完成将通过专业知识和现有的 筛选和基因组基础设施在共同导师的实验室，并利用独特的共同临床 已经由密切的机构合作者建立的平台。这项研究将建立一个病人来源的 用于询问CRT诱导的肿瘤演变的平台，建立科学利基以促进成功 在向科学独立过渡的过程中。