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Extracellular RNA in Drug and Diagnostic Development

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Extracellular RNAs (exRNAs) found in biofluids are a rich source of information about cellular processes in both health and disease. In particular, exRNAs enclosed in extracellular vesicles and therefore protected from degradation, are involved in intercellular communication and may serve as diagnostic and prognostic biomarkers of cancer, cardiovascular and neurodegenerative diseases. Cambridge Healthtech Institute’s Second Annual Extracellular RNA in Drug and Diagnostic Development meeting will present the latest research in this emerging area of non-invasive diagnostics, including exosomes and microvesicles, circulating microRNA and other non-coding RNA, and issues of standardization, profiling, and data analysis.

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Tuesday, April 5

12:00 pm Conference Registration


Extracellular RNA as Biomarkers and Diagnostics

1:25 Chairperson’s Opening Remarks
Frank Slack, Ph.D., Director, Institute for RNA Medicine, Department of Pathology, BIDMC Cancer Center, Harvard Medical School

1:30 OncomiRs as Functional Biomarkers for Cancer

Frank Slack, Ph.D., Director, Institute for RNA Medicine, Department of Pathology, BIDMC Cancer Center, Harvard Medical School

MicroRNAs are excellent candidates for human biomarker studies because their signature short sequences can be easily identified, they are stable in tissue and body fluids, and their expression patterns can be rigorously detected and quantified without harm to the individual. MicroRNAs have been found in multiple body fluids, such as serum and plasma, making them an attractive option for studying non-invasive, blood-based biomarkers. These circulating miRNAs are resistant to RNases and are in fact very stable in an extracellular environment, as they can be packaged in microvesicles, exosomes, or apoptotic bodies. Indeed, profiles of plasma and serum miRNAs have been linked to numerous cancers, and diabetes, indicating that miRNAs are a new class of blood-based biomarkers of human diseases.

2:00 Circulating miRNA as a Disease Marker in Multiple Sclerosis

Roopali Gandhi, Ph.D., Assistant Professor, Neurology, Harvard Medical School; Head, MS Biomarkers, Brigham & Women's Hospital

2:30 microRNAs in Cerebrospinal Fluid as Biomarkers for Alzheimer’s Disease

Julie Saugstad, Ph.D., Associate Professor, Anesthesiology & Perioperative Medicine, Oregon Health & Science University

Alzheimer’s disease (AD) is the most common form of dementia. There are currently no clinical biomarkers to confirm the onset of AD, but such a tool would allow earlier initiation of treatments that can slow disease progression. Here, we describe our efforts to identify extracellular microRNAs circulating in cerebrospinal fluid obtained from living donors to serve as biomarkers for AD using quantitative RT-PCR platforms for discovery and validation studies.

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 The NIH Extracellular RNA Communication Program: exRNA for Therapy and Biomarker Development
Tania Lombo, Ph.D., Scientific Program Manager, National Center for Advancing Translational Sciences, National Institutes of Health

4:15 Featured Late-Breaking Presentation: microRNA-Mediated (Re-) Programming of the Immune System

Stefan A. Muljo, Ph.D., Chief, Integrative Immunobiology Unit, NIAID, Laboratory of Immunology, National Institutes of Health


Transcriptome Analysis and Data Resources

4:45 Transcriptome Analysis

Mark B. Gerstein, Ph.D., Albert L. Williams Professor, Biomedical Informatics, Yale University

This presentation will cover RNA-seq pipelines, RNA-seq clustering techniques, and privacy considerations for RNA-seq data.

5:15 Exploring exRNA Function via RNA-Seq Pipelines, Pathway Analysis Tools, and Data Resources Developed by the exRNA Communication Consortium (ERCC)

Matthew Roth, Ph.D., Assistant Professor & Co-Director, Bioinformatics Research Lab, Baylor College of Medicine; Data Management & Resource Repository of the Extracellular RNA Consortium (NIH)

The NIH funded extracellular RNA Communication Consortium (ERCC) brings together experts in exRNA biology, human disease, bioinformatics, biomarker discovery, and therapeutic development to better understand exRNA biology and potential clinical applications. A key ERCC mission is the development of analytical pipelines and data resources for the broader scientific community. A description of these resources and their application to exRNA analyses will be presented.



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Wednesday, April 6

8:00 am Morning Coffee


Potential of Extracellular Vesicles as Biomarkers and Therapeutics

8:25 Chairperson’s Remarks

Peter J. Quesenberry, M.D., Professor, Medicine, Brown University

8:30 miRNA as a Vesicular Therapeutic

Peter J. Quesenberry, M.D., Professor, Medicine, Brown University

Extracellular vesicles represent a new mode of intercellular communication. We have studies showing that “toxic” endothelial progenitors induced by vesicle exposure can induce pulmonary hypertension (PH) and that mesenchymal stem cell (MSC) derived vesicles can reverse PH. Similarly, normal or MSC vesicles can reverse ischemia-reperfusion renal injury and radiation injury to murine marrow stem cells. MSC or normal vesicles can also reverse the malignant phenotype of prostate and colorectal cancer.

9:00 Oncogene Patterning of the Tumor Microenvironment via exRNA and Exosomes

James G. Patton, Ph.D., Professor, Biological Sciences, Vanderbilt University

Mutant KRAS induces trafficking of EGF receptor (EGFR) and the EGFR ligand amphiregulin to exosomes and drastically changes exosomal protein content, leading to activities that can alter the tumor microenvironment. We characterized small RNAs from cells and matched exosomes that differ only in KRAS status. Exosomal small RNA profiles were distinct from cellular profiles, and mutant KRAS exosomes clustered separately from wild-type KRAS exosomes. miR-100 levels were increased in mutant KRAS cell-derived exosomes and delivery of exosomes with miR-100 downregulated mTOR in recipient cells. Selective trafficking of miRNAs into exosomes appears to be dependent on KRAS-MEK signaling effects on Argonaute 2, a key component of RNA-Induced Silencing Complexes. Besides extracellular RNA transfer, we find that mutant KRAS derived exosomes confer metabolic-altering activity to cells in vitro and in vivo. These findings have implications for non-cell autonomous effects of cancer on the tumor microevironment and the cancer field effect.

9:30 Extracellular Vesicles in Cancer Diagnosis, Prognosis and Epidemiology: Are We Ready for the Prime Time?

Mukesh Verma, Ph.D., Chief, Methods and Technologies Branch, National Cancer Institute, National Institutes of Health

Both normal and diseased cells continuously shed extracellular vesicles (EVs) into extracellular space, and the EVs carry molecular signatures and effectors of both health and disease. EVs reflect dynamic changes that are occurring in cells and tissue microenvironment in health and at a different stage of a disease. EVs are capable of altering the function of the recipient cells. Trafficking and reciprocal exchange of molecular information by EVs among different organs and cell types have been shown to contribute to horizontal cellular transformation, cellular reprogramming, functional alterations, and metastasis. EV contents may include tumor suppressors, phosphoproteins, proteases, growth factors, bioactive lipids, mutant oncoproteins, oncogenic transcripts, microRNAs, and DNA sequences. Therefore, the EVs present in biofluids offer unprecedented, remote, and non-invasive access to crucial molecular information about the health status of cells, including their driver mutations, classifiers, molecular subtypes, therapeutic targets, and biomarkers of drug resistance. In addition, EVs may offer a non-invasive means to assess cancer initiation, progression, risk, survival, and treatment outcomes. The goal of this review is to highlight the current status of information on the role of EVs in cancer, and to explore the utility of EVs for cancer diagnosis, prognosis and epidemiology.

10:00 Networking Coffee Break

10:30 Large Oncosomes: New Frontiers for Cell-to-Cell Communication in Cancer

Dolores Di Vizio, M.D., Ph.D., Associate Professor, Surgery, Biomedical Sciences, Pathology & Laboratory Medicine, Cedars-Sinai Medical Center; Associate Professor, Medicine, University California, Los Angeles; Assistant Professor, Boston Children’s Hospital, Harvard Medical School

Our team recently reported that highly metastatic cells export large (1-10 µm diameter) bioactive EVs (large oncosomes) that originate from the shedding of bulky membrane protrusions from the plasma membrane. We have demonstrated that the abundance of large oncosomes in the circulation and in tissues correlate with advanced disease in mouse models and human subjects. Large-scale profile analyses demonstrate that large oncosomes represent a novel population of EVs enriched in tumor-derived molecules. Large oncosomes are thus valuable candidates for new biomarker profiles to be developed using tissue- and blood-based assays in combination.

11:00 Clinical Evaluation of Circulating Biomarkers in Precision Medicine

Shidong Jia, Ph.D., Founder & CEO, Predicine

The enumeration and characterization of circulating tumor cells (CTCs), exosomes and circulating tumor-free DNA (ctDNA) in the peripheral blood provide important prognostic and diagnostic information in personalized cancer care. Specific examples will be shown to demonstrate the opportunities and challenges for the development of circulating biomarkers in cancer.

11:30 Extracellular RNA Profiles Predictive of Human Allograft Status

Manikkam Suthanthiran, M.D., Stanton Griffis Distinguished Professor, Medicine; Chief, Division of Nephrology and Hypertension, Weill Cornell Medical College

Liver transplantation is the only lifesaving therapy for patients with irreversible liver failure. A frequent post-transplant complication is acute rejection, currently diagnosed by invasive needle biopsy of the liver allograft. Because miRNAs may serve as biomarkers of clinical disease, we investigated whether circulating extracellular miRNAs in the serum of liver transplant recipients predict human liver transplant status. Our findings support the hypothesis that measurement of circulating levels of extracellular miRNAs offers a noninvasive means of monitoring lifesaving liver transplants.

12:00 Featured Late-Breaking Presentation: microRNAs and the Immunometabolic Response to Viral Infection

John Paul Pezack, Ph.D., Professor, Chemistry & Biomolecular Science, University of Ottawa

12:30 pm Enjoy Lunch on Your Own


lncRNA and the Promise of ncRNAs

1:55 Chairperson’s Remarks

Da-Zhi Wang, Ph.D., Associate Professor, Cardiovascular Research Division, Department of Cardiology, Boston Children’s Hospital, Harvard Medical School

2:00 ncRNAs in Cardiovascular Diseases

Da-Zhi Wang, Ph.D., Associate Professor, Cardiovascular Research Division, Department of Cardiology, Boston Children’s Hospital, Harvard Medical School

Thousands of long non-coding RNAs (lncRNAs) have been discovered; however, the role of most lncRNAs in heart failure remains largely unknown. We performed RNA deep sequencing from cardiac samples of patients with ICM and controls. Expression correlation coefficient analyses revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. Gain- and loss-of function studies demonstrate that lncRNAs are important regulators of fibrosis. Our results indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ischemic cardiomyopathy.

2:30 Long Non-Coding RNAs and Tumor Suppression

Nadya Dimitrova, Ph.D., Assistant Professor, Molecular, Cellular, and Developmental Biology, Yale University

There is an unmet need to gain a deeper understanding of the in vivo biology of lncRNAs that are deregulated in disease states, such as cancer. Our laboratory uses genetic approaches to study a subset of lncRNAs that are directly regulated by the important tumor suppressor protein, p53. Our analyses reveal that lncRNAs influence the expression of proteins in the p53 pathway and play key roles in the physiological response to stress and in tumor suppression.

3:00 Using ncRNAs to Identify Cancer Cell Vulnerabilities

Alexander Pertsemlidis, Ph.D., Associate Professor, Pediatrics and Cellular & Structural Biology, University of Texas Health Science Center at San Antonio

To identify ncRNAs that regulate tumor cell viability, we have combined a high-throughput screening platform with libraries of chemically synthesized ncRNA mimics and inhibitors. Candidate targets are validated using qRT-PCR, protein quantification, and luciferase reporter assays. The response of cancer cells to perturbations in candidate ncRNA levels is assessed through flow cytometric analysis of cell cycle phase distribution and through colony formation and caspase activation assays, and validated in mouse xenograft models. We have identified ncRNA mimics and inhibitors that have significant effects on cell viability and drug response. While these ncRNAs may have intrinsic value as biomarkers or therapeutic agents, the vulnerabilities that they uncover are also of value, in that they can be targeted directly with pathway-specific perturbations.

3:30 Close of Conference



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