Understanding the Relationship of Repeat Expression and Metastasis

了解重复表达与转移的关系

基本信息

批准号：
10380304
负责人：
Benjamin Greenbaum
金额：
$ 13.78万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380304
关键词：
Affect Agar Anoikis Antineoplastic Agents Biological Assay Cancer Biology Cancer Center Cancer Patient Cell Count Cell Death Cell Line Cells Clinical Code Collection Colorectal Colorectal Cancer DNA Devices Elements Embryonic Development Endogenous Retroviruses Foundations Funding Gene Expression Gene Expression Profile Genes Genetic Transcription Grant Histologic Human Image Image Analysis Immune Immune response In Vitro Lamivudine Lesion Link Liver Lung Malignant Neoplasms Metastatic Neoplasm to the Liver Metastatic to Microfluidics Modality Modeling Neoplasm Circulating Cells Neoplasm Metastasis Normal tissue morphology Nucleosides Organ Parents Patients Phase II Clinical Trials Pre-Clinical Model Primary Neoplasm Progression-Free Survivals RNA Repetitive Sequence Resected Resistance Retrotransposition Reverse Transcriptase Inhibitors Reverse Transcription Role Sampling Signal Transduction Site Slide Solid Source Specimen Suggestion Tail Untranslated RNA Up-Regulation Veins Virus Virus Diseases anti-cancer arm cancer care cancer cell cancer genome clinical care colon cancer cell line colon cancer patients colorectal cancer metastasis differential expression digital epithelial to mesenchymal transition in vivo luminescence matrigel metastatic colorectal metastatic process mortality mouse model nano-string neoplastic cell novel diagnostics novel therapeutics pre-clinical programs quantitative imaging response single-cell RNA sequencing stem cells transcriptome sequencing transcriptomics tumor tumor-immune system interactions

项目摘要

PROJECT SUMMARY Metastasis is the cause of mortality in the majority of solid cancers including colorectal cancer. Understanding the metastatic process will open the door to developing new therapeutic and diagnostic modalities for the care of cancer patients. Analysis of circulating tumor cells (CTCs) in cancer mouse models has revealed the abundant expression of repetitive element RNAs implicating their role in the metastatic cascade. Many of these repeat RNAs are capable of retrotransposition through reverse transcription (RT), which leads to alterations in the cancer genome. Our preclinical cell line and mouse models have demonstrated the ability of these endogenous RT to be blocked by nucleoside reverse transcriptase inhibitors (NRTIs) commonly used for viral infections. Interestingly, we have found anti-cancer effects of NRTIs in multiple colorectal cancer (CRC) preclinical models that led to a Phase II clinical trial of the NRTI 3TC in metastatic CRC patients. In this proposal, we plan to: 1) Understand the effects of 3TC on in vitro and in vivo metastatic capability in CRC 2) Compare the expression of repeat RNAs in paired primary tumor and liver metastases resected from patients with CRC 3) Characterize the dynamics of CTCs in patients treated with 3TC in the phase II clinical trial

项目概要转移是包括结直肠癌在内的大多数实体癌的死亡原因。理解转移过程将为开发新的治疗和诊断方法打开大门的癌症患者。对癌症小鼠模型中循环肿瘤细胞 (CTC) 的分析揭示了丰富的重复元件 RNA 的表达表明它们在转移级联中的作用。其中很多都是重复的 RNA 能够通过逆转录 (RT) 进行逆转录转座，从而导致癌症基因组。我们的临床前细胞系和小鼠模型已经证明了这些内源性的能力 RT 可被常用于病毒感染的核苷逆转录酶抑制剂 (NRTI) 阻断。有趣的是，我们在多种结直肠癌 (CRC) 临床前模型中发现了 NRTI 的抗癌作用这促成了 NRTI 3TC 在转移性 CRC 患者中的 II 期临床试验。在本提案中，我们计划： 1) 了解3TC对CRC体外和体内转移能力的影响 2) 比较从患者身上切除的配对原发肿瘤和肝转移瘤中重复RNA的表达与CRC 3) 描述 II 期临床试验中接受 3TC 治疗的患者 CTC 的动态特征