Understanding the Relationship of Repeat Expression and Metastasis

项目总结 转移是包括结直肠癌在内的大多数实体肿瘤的死亡原因。理解 转移过程将为开发新的治疗和诊断方法打开大门。 癌症患者。对肿瘤小鼠模型中循环肿瘤细胞(CTCs)的分析揭示了丰富的 重复元件RNA的表达暗示其在转移级联反应中的作用。其中很多都是重复的 RNA能够通过逆转录(RT)进行逆转录，这会导致 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 逆转录酶被通常用于病毒感染的核苷逆转录酶抑制剂(NRTI)阻断。 有趣的是，我们在多发性结直肠癌(CRC)临床前模型中发现了NRTI的抗癌作用 这导致了NRTI 3TC在转移性结直肠癌患者中的第二阶段临床试验。在这项建议中，我们计划： 1)了解3TC对结直肠癌体外和体内转移能力的影响 2)比较配对的原发灶和肝转移瘤组织中重复序列RNA的表达 使用CRC 3)在II期临床试验中描述接受3TC治疗的患者的CTCs的动力学特征

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