The role of non-coding RNAs in metastasis and therapy escape

近年来，几种低剂量节拍疗法（LDM）方案在癌症治疗中取得了成功，特别是对于标准高剂量化疗难治性患者、晚期疾病和高剂量靶向治疗后的维持治疗。迄今为止，节拍疗法的已知机制包括抑制肿瘤血管生成、刺激抗癌细胞毒性T细胞免疫应答、抑制缺氧诱导因子-1 α（HIF-1）、直接肿瘤细胞靶向效应和诱导肿瘤休眠。尽管如此，对LDM的分子基础知之甚少，例如调节RNA如microRNA（miRNA）、环状RNA和长非编码RNA在LDM治疗期间的作用。我们项目的总体目标是描述LDM治疗期间原发性肿瘤和转移中的非编码RNA。在第一个资助期内，我们进行了非编码RNA筛选和数据分析，并开始在分子水平上表征极具前景的非编码RNA。我们在下一个资助期的工作重点是进一步的功能表征以及基于非编码RNA的适应效应和LDM治疗期间的治疗逃避。我们将继续使用乳腺癌的BalbNeuT小鼠模型（中心小鼠项目）、异种移植物HT29.hCG.Luc SCID和结肠癌的同基因CMT93.hCG.Luc C57 BL/6模型。我们奋进的最终目标之一是找到和操纵非编码RNA，并确定LDM治疗的有益效果。

In recent years, several regimes of low-dose metronomic therapy (LDM) have been successful in cancer therapy especially for patients refractory to standard high-dose chemotherapy, for advanced stage disease and in maintenance therapy following high dose and targeted treatments. So far, known mechanisms of metronomic therapy include suppression of tumor-angiogenesis, stimulation of anticancer cytotoxic T-cell immune responses, inhibition of the hypoxia inducible factor-1 alpha (HIF-1), direct tumor cell targeting effects and the induction of tumor dormancy. Despite this, little is known about the molecular basis of LDM, e.g. the role of regulatory RNAs such as microRNAs (miRNAs), circular RNAs and long non-coding RNAs during LDM therapy. The general goal of our project is to characterize non-coding RNAs in primary tumors and metastasis during LDM therapy. During the first funding period, we have performed non-coding RNA screening and data analysis and started to characterize highly promising non-coding RNAs on a molecular level. The focus of our efforts in the next funding period is on further functional characterization as well as on non-coding RNA-based adaptation effects and therapy escape during LDM therapy. We will continue to use the BalbNeuT mouse model of breast cancer (central mouse project), the xenograft HT29.hCG.Luc SCID and the syngeneic CMT93.hCG.Luc C57BL/6 models of colon cancer. One of the ultimate goals of our endeavor is to find and manipulate a non-coding RNA and identify beneficial effects for LDM therapy.