The overall goal of this application is to identify and qualify exosomal non-coding RNA based biomarkers in the circulation to detect early stage disease in patients at risk, to predict recurrence after surgery and to monitor response to therapy in patients with hepatocellular cancer (HCC). The incidence of this cancer is increasing and survival remains poor. Early detection of HCC is essential to survival, yet current biomarkers such as AFP lack the sensitivity to sufficiently detect early stage cancer amenable to surgical cure. Our preliminary studies have identified several microRNA and long-non-coding RNA that are selectively enriched within exosomes released from HCC cells. Moreover, we have cloned a novel long non-coding RNA gene, TUC339 that is very highly enriched in exosomes released from HCC cells, and that can be detected in serum from patients with HCC. We hypothesize that tumor specific non-coding RNA that are selectively released within exosomes into the circulation can be detected to provide highly specific biomarkers for HCC. This project will test this hypothesis using a rigorous two phase biomarker development process to evaluate the utility of exosomal TUC339 and to identify other extracellular non-coding RNA (exRNA) as diagnostic and prognostic biomarkers of HCC. The goal of the first phase will be to identify lead candidates and to develop digital PCR based assays for their detection whereas the goals of the second phase will be to validate the clinical utility of promising exRNA candidates by prospectively validating their capability for diagnosis and as biomarkers of recurrence or treatment response. The study design includes (a) evaluation of identified exRNA candidates and further discovery studies for known or novel long non-coding RNA, (b) explicit biospecimen collection and processing, (c) a multi-stage integrated approach with a prospective case control study, comparison with independently obtained case-control reference samples, and an independent multi-center validation study either as part of a planned on-going study (HEDS) or through a new consortium-based study. Additionally, we will prospectively evaluate exRNA as predictors of recurrence or treatment response. Through these efforts, we expect to develop novel analytical assays for circulating exRNA and to identify a clinically relevant biomarker that will be useful as a diagnostic, prognostic or treatment response marker for patients with HCC.
A goal of this project is to identify new RNA markers circulating within exosomes for early diagnosis and improved care of liver cancer, and thereby to improve the care and outcomes from liver diseases. These studies will identify new non-coding RNA that will be clinically useful disease biomarkers, as well as develop novel sensitive assays for their detection. The results will have a broader impact by increasing basic knowledge about non-coding RNA and their detection and use as biomarkers for other diseases.
|Godoy, Paula M; Bhakta, Nirav R; Barczak, Andrea J et al. (2018) Large Differences in Small RNA Composition Between Human Biofluids. Cell Rep 25:1346-1358|
|Haga, Hiroaki; Yan, Irene K; Takahashi, Kenji et al. (2017) Extracellular Vesicles from Bone Marrow-Derived Mesenchymal Stem Cells Improve Survival from Lethal Hepatic Failure in Mice. Stem Cells Transl Med 6:1262-1272|
|Yuan, Tiezheng; Huang, Xiaoyi; Woodcock, Mark et al. (2016) Plasma extracellular RNA profiles in healthy and cancer patients. Sci Rep 6:19413|
|Laurent, Louise C; Abdel-Mageed, Asim B; Adelson, P David et al. (2015) Meeting report: discussions and preliminary findings on extracellular RNA measurement methods from laboratories in the NIH Extracellular RNA Communication Consortium. J Extracell Vesicles 4:26533|
|George, Joseph; Patel, Tushar (2015) Noncoding RNA as therapeutic targets for hepatocellular carcinoma. Semin Liver Dis 35:63-74|
|Kim, Dae-Kyum; Lee, Jaewook; Kim, Sae Rom et al. (2015) EVpedia: a community web portal for extracellular vesicles research. Bioinformatics 31:933-9|
|Haga, Hiroaki; Yan, Irene K; Takahashi, Kenji et al. (2015) Tumour cell-derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth. J Extracell Vesicles 4:24900|
|Haga, Hiroaki; Patel, Tushar (2015) Molecular diagnosis of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci 22:114-23|
|Patel, Tushar; Harnois, Denise (2014) Assessment of response to therapy in hepatocellular carcinoma. Ann Med 46:130-7|
|Takahashi, Kenji; Yan, Irene K; Kim, Chaeyoung et al. (2014) Analysis of extracellular RNA by digital PCR. Front Oncol 4:129|
Showing the most recent 10 out of 17 publications