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.

项目摘要/摘要局部晚期直肠癌，通过扩散到淋巴结或通过完整直肠壁扩展定义每年在15,000多名美国患者中被诊断出厚度。本地直肠的标准治疗美国癌症涉及化学疗法和放射疗法（化学放疗，CRT）整个直肠。患者可能会遇到不太明显的手术后后果，例如永久性肺切开术或厌氧功能改变。鉴于此，许多持续的研究集中于避免的策略手术干预可能仅用CRT治愈的患者子集。在手术时，10- 30％的肿瘤被CRT放射（即它们表现出病理完全反应），而其他肿瘤几乎没有反应。这种响应中的可变性尚不完全理解，但可能与一个肿瘤可能包含许多不同的肿瘤细胞亚群，所有肿瘤的基因型都不同和表观遗传（或非遗传）特征。这些潜水员亚群和可变的遗传/表观遗传学特征可以相互作用，从而导致动态和不断发展的肿瘤细胞网络，该网络知之甚少。在癌症数量增加，有证据支持治疗引起的进化的出现 “陷阱”或“ Collatell敏感性”，其中一种对一种疗法的抗性会导致对另一种疗法的敏感性。这是否发生在直肠癌中，以及如何将其利用为治疗策略，尚不清楚。解决这些问题，选择代表性的实验模型至关重要。那是当前的提议利用已经建立的共同链式管道，从中使用患者衍生的肿瘤样品生成配对的，患者特异性的类器官和异种移植模型。两种广泛的分析方法将是旨在确定CRT诱导的肿瘤演化的趋势，并阐明了潜在的协同方法改善CRT响应。特定的目标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与谱系结合的高级方法跟踪。特定目标2员工创新的迭代配对CRISPR/高通量药物屏幕方法确定在CRT处理的直肠癌中不断发展的侧外敏感性。为了验证两个目标中的发现，将利用先进的患者衍生的直肠癌类器官和异种移植模型。研究，科学指导和职业发展将由导师和合作者的专家小组支持结构化培训计划。成功完成这两个目标将由专业知识和现有筛查和基因组基础设施在联合会实验室中，并利用独特的共同临床平台已经由密切机构合作者建立。这项研究将建立一个衍生的患者询问CRT诱导的肿瘤进化的平台，建立科学利基以促进成功在过渡到科学独立的过程中。