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

基本信息

批准号：
10704660
负责人：
Christine Elissa Eyler
金额：
$ 24.08万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10704660
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 Combination Drug Therapy 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 Institution 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 Variant Xenograft Model advanced disease 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 novel therapeutic intervention 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 tumor eradication

项目摘要

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.

项目概要/摘要局部晚期直肠癌，定义为扩散至淋巴结或延伸至整个直肠壁每年有超过 15,000 名美国患者被诊断为局部晚期直肠癌的标准治疗。在美国，癌症在手术切除之前需要进行化疗和放疗（放化疗，CRT）患者可能会经历不良的术后后果，例如永久性的。鉴于此，许多正在进行的研究都集中在避免结肠造口术或改变肛门直肠功能的策略上。对可能仅通过 CRT 治愈的患者进行手术干预在手术时，10-。 30% 的肿瘤通过 CRT 被根除（即，它们表现出病理学完全缓解），而其他肿瘤肿瘤几乎没有反应，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，一种肿瘤可能包含许多不同的肿瘤细胞亚群，所有亚群都具有不同的基因型和表观遗传（或非遗传）特征。这些特征可以相互作用，从而形成一个动态且不断发展的肿瘤细胞网络，但人们对此知之甚少。随着癌症数量的增加，有证据支持治疗诱导的进化的出现 “陷阱”或“附带敏感性”，即对一种疗法的抵抗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，以及如何将其纳入治疗策略尚不清楚。对于这些问题，选择一个有代表性的实验模型至关重要。利用已经建立的联合临床管道，其中患者来源的肿瘤样本被用来生成配对的、患者特异性的类器官和异种移植模型将是两种广泛的分析方法。旨在确定 CRT 诱导的肿瘤进化趋势并阐明潜在的协同方法改善 CRT 反应。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 Specific Aim 2 采用创新的迭代配对 CRISPR/高通量药物筛选方法。确定 CRT 治疗的直肠癌中不断变化的附带敏感性以验证这两个目标的发现，将利用先进的源自患者的直肠癌类器官和异种移植模型进行研究、科学研究。指导和职业发展将得到导师和合作者专家小组以及专业知识和现有的培训计划将促进这两个目标的成功完成。共同导师实验室中的筛选和基因组基础设施，并利用独特的联合临床密切的机构合作者已经建立了平台，这项研究将建立一个源自患者的平台。用于探究 CRT 诱导的肿瘤进化的平台，建立科学利基以促进成功在向科学独立过渡期间。