Understanding the Relationship of Repeat Expression and Metastasis

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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