Extracellular Biomarkers Summit

March 16-18, 2015Hyatt Regency Cambridge | Cambridge, MA

DINNER COURSES

MARCH 16

⊲ Systems Biology, Evidence Synthesis and in silico Discovery Approaches to microRNA Biomarkers

⊲ Executive ThinkTank: Development of Exosome-Based Diagnostics

MARCH 17

⊲ RNA-Seq: A Fundamental Guide to the Field

⊲ Circulating Nucleic Acid Biomarkers for Development of Non-Invasive Prenatal Tests

ExtracellularBiomarkers.com

FEATURED SPEAKERS

Carlo M. CroceDirector, Genetics InstituteThe Ohio State University

Susan FreierVice PresidentIsis Pharmaceuticals

Ajay GoelDirector, Cancer PreventionBaylor Research Institute

Raghu KalluriChair, Cancer BiologyMD Anderson Cancer Center

Frank SlackDirector, Institute for RNA Medicine Beth Israel Deaconess Medical Center

Nicole Meisner-KoberSenior Investigator, RNA BiologyNovartis

EXTRACELLULAR BIOMARKERS SUMMIT

Register Early for Maximum Savings

microRNA as Biomarkers and Diagnostics

Long Non-Coding RNA in Cancer

Exosomes and Microvesicles as Biomarkers and Diagnostics

Extracellular RNA in Drug and Diagnostic Development

Organized byCambridge Healthtech Institute

2 | ExtracellularBiomarkers.com

Sponsor & Exhibitor Opportunities CHI offers comprehensive packages that can be customized to your budget and objectives. Sponsorship allows you to achieve your goals before, during, and long after the event. Packages may include presentations, exhibit space and branding, as well as the use of delegate lists. Signing on early will maximize your exposure to qualified decision-makers and drive traffic to your website in the coming months.

Podium Presentations — Available within Main Agenda! Showcase your solutions to a guaranteed, targeted audience through a 15- or 30-minute presentation during a specific program, breakfast, lunch, or a pre-conference workshop. Package includes exhibit space, on-site branding, and access to cooperative marketing efforts by CHI. Lunches are delivered to attendees who are already seated in the main session room. Presentations will sell out quickly! Sign on early to secure your talk.

Invitation-Only VIP Dinner/Hospitality Suite Select specific delegates from the pre-registration list to attend a private function at an upscale restaurant or a reception at the hotel. From extending the invitations, to venue suggestions, CHI will deliver your prospects and help you make the most of this invaluable opportunity.

Focus Group CHI will gladly provide you the opportunity of running a focus group on-site. This exclusive gathering can be useful to conduct market research, collect feedback on a new product idea, and collect marketing intelligence from industry experts on a specific topic.

User Group Meeting/Custom Event Co-locate your user group meeting or custom event. CHI will help market the event, manage logistical operations, develop the agenda, and more. CHI can handle the entirety of the meeting or select aspects.

Exhibit Exhibitors will enjoy facilitated networking opportunities with qualified delegates, making it the perfect platform to launch a new product, collect feedback, and generate new leads. Exhibit space sells out quickly, so reserve yours today!

Additional branding and promotional opportunities are available, including:

• Conference Tote Bags• Literature Distribution (Tote Bag Insert or Chair Drop)• Badge Lanyards• Program Guide Advertisement• Padfolios and More...

Hyatt Regency Cambridge575 Memorial DriveCambridge, MA 02139Phone: 1-888-421-1442

Discounted Room Rate: $209 s/dDiscounted Room Cut-off Date: February 16, 2015

Please call the hotel directly to reserve your sleeping accommodations. You will need to identify yourself as a Cambridge Healthtech Institute conference attendee to receive the discounted room rate with the host hotel. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space- and rate-availability basis. Rooms are limited, so please book early.

Top Reasons to Stay at the Hyatt Regency Cambridge:

• Complimentary internet in guestrooms

• Hotel will provide shuttle to/from Kendall and Harvard Square each evening from 6-10pm

• Approximately 15 minutes from Boston Logan International Airport

• Sundeck overlooks the beautiful Boston skyline along the Charles River

Car Rental Discounts:

Car rental discounts are available. Visit ExtracellularBiomarkers.com for details.

Hotel & Travel

For additional information, please contact:

Carolyn Benton, Business Development Manager781-972-5412 | [email protected]

About the EventExtracellular Biomarkers Summit, the newest addition to Cambridge Healthtech Institute’s notable biomarker and diagnostics portfolio, merges the well-established microRNA as Biomarkers and Diagnostics conference with focused discussions on other leading areas of research: the role of circulating microRNA, exosomes and microvesicles, long non-coding RNA and extracellular RNA in cancer and other diseases, as well as their potential to serve as biomarkers in drug and diagnostic development. Discussions will include the isolation and characterization of exosomes and exRNA, including expression profiling and sequencing of exRNA; understanding the role of miRNA, lncRNA, and exosomes in disease mechanism, tumor metastasis, and intracellular communication; their potential as biomarkers in drug development, drug toxicity assessment, and patient stratification; and finally, their role as circulating biomarkers for disease diagnosis and prognosis.

Please join us to gain comprehensive coverage of extracellular biomarkers and hear from industry leaders on cutting-edge research, technologies and applications.


Dinner Short Courses*MONDAY, MARCH 16, 6:30-9:30 PM

⊲ SC1: Systems Biology, Evidence Synthesis and in silico Discovery Approaches to microRNA Biomarkers

Instructors:Christos Argyropoulos, M.D., Ph.D., Assistant Professor, Nephrology, Department of Internal Medicine, University of New Mexico School of MedicineJohn Chevillet, Ph.D., Postdoctoral Research Fellow, Laboratory of Leroy Hood, Institute for Systems Biology

There currently exists no standard systematic way to identify candidate microRNAs for experimental evaluation and verification of their utility as disease biomarkers. In this course we will present a putative framework for the identification of candidate circulating microRNA biomarkers, based on in silico, systems biology and quantitative evidence synthesis techniques. We will discuss the implementation of circulating miRNA studies and examine relevant workflows, specimen collection and handling, quantification and data analysis techniques.

⊲ SC2: Executive ThinkTank: Development of Exosome-Based Diagnostics

As the demand for more cost-effective treatments increases and the benefit of personalized medicine is clear, the goal of developing accurate, non-invasive diagnostics becomes ever more urgent. Exosomes are especially useful for clinical diagnostics because of their tissue specificity and stability in biofluids, yet issues still remain in their development as diagnostics. What are the optimal methods for isolation and purification? What assays should be used to quantitate exosomal biomarkers? How should exosomal biomarkers be normalized? What theoretical and logistical challenges are bottlenecks for exosomal biomarker development and qualification? These topics and others will be explored in this moderated panel discussion.

Moderator:Peter Yuen, Ph.D., Staff Scientist, Renal Diagnostics & Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

Panelists:• Clark C. Chen, M.D., Ph.D., Associate Professor and Chief, Stereotactic

and Radiosurgery; Vice-Chairman, Academic Affairs, Neurosurgery, University of California, San Diego

• Hakho Lee, Ph.D., Assistant Professor, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School

• Radha Munagala, Ph.D., Assistant Professor, Department of Medicine, James Graham Brown Cancer Center, University of Louisville

• Qiang Shi, Ph.D., Visiting Scientist, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration

• David T.W. Wong, D.M.D., DMSc, Professor and Associate Dean of Research, UCLA School of Dentistry; Director, Dental Research Institute

TUESDAY, MARCH 17, 6:00-9:00 PM

⊲ SC3:RNA-Seq: A Fundamental Guide to the Field

Instructor: Seth Crosby, M.D., Director, Partnerships & Alliances, Washington University School of Medicine

A practical introduction for those considering the RNA-seq journey, and what’s new for those who have already set off.

Whether or not you are new to the field, this all-encompassing workshop will give detailed insight, in an interactive format, across the entire RNA-Seq landscape. RNA sources and preparation, the myriad library construction options, sequencing: to pair or not to pair, and the world of analysis, from the Tuxedo suite to STAR and beyond – all will be covered and discussed in this complete learning experience.

Leave this workshop with:• A comprehensive understanding of the RNA-Seq landscape• Further development of the questions to ask when considering

RNA-Seq• A review of the bench and informatic technologies that are right for

your specific research needs

⊲ SC4:Circulating Nucleic Acid Biomarkers for Development of Non-Invasive Prenatal Tests

Instructor: Louise C. Laurent, M.D., Ph.D., Assistant Professor, Department of Reproductive Medicine, University of California San Diego Health Science

This course will review both currently available technologies and potential future approaches based on non-invasive analysis of circulating fetal nucleic acids (CNAs) in the maternal blood for detection of pregnancies affected by fetal genetic abnormalities and prediction of adverse pregnancy outcomes, such as preterm birth and pre-eclampsia. The majority of these tests use next-gen sequencing for quantitative evaluation of specific sequences in circulating fetal DNA or RNA (notably, RNA-based strategies are all still in the research and development stage). Technical considerations in assay development for C-based prenatal testing applications will also be covered.


*Separate registration required


microRNA as Biomarkers and DiagnosticsE L E V E N T H A N N U A L

MONDAY, MARCH 16

7:00 am Conference Registration and Morning Coffee

8:00 Welcome Remarks from Conference Director

Exosomal RNA/DNA in Cancer8:10 Chairperson’s Opening RemarksJanusz Rak, M.D., Ph.D., McGill University, Montreal Children’s Hospital

8:15 The Biology and Functional Contribution of Exosomes in Cancer Progression and MetastasisRaghu Kalluri, M.D., Ph.D., Professor and Chair, Cancer Biology, University of Texas MD Anderson Cancer Center

8:40 Exosomic microRNAs Affect the Biology of the Tumor MicroenvironmentMuller Fabbri, M.D., Ph.D., Assistant Professor, Pediatrics and Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine, Children’s Hospital Los AngelesmicroRNAs (miRNAs) are small non-coding RNAs which regulate the expression of about 30% of genes. miRNAs are secreted by cancer cells within exosomes, nanovesicles able to transfer intercellularly their content of DNA, RNA and proteins. We and others showed that specific exosomic miRNAs released by cancer cells can bind to receptors in surrounding cells and affect the biology of the tumor microenvironment. This lecture will highlight how interfering with this exosomic-miRNA-mediated cross-talk might lead to new anti-cancer treatments.

9:05 Exosomal microRNAs in Urine - Promising Biomarkers for Prostate Cancer

Sponsored by

Peter Mouritzen, Vice President Research and Development, Exiqon A/SWe have developed a highly sensitive LNA™-based qPCR platform for microRNA detection, which enables profiling in biofluids where microRNA levels are extremely low. The qPCR system has been applied to identify promising diagnostic prostate cancer biomarkers in exosomes from urine purified with our recently developed exosome enrichment kit. In general, sample and data qualification is critical in biofluids to secure high quality data, which we will demonstrate.

9:20 Networking Coffee Break

microRNA Biomarkers in Drug Development9:50 Chairperson’s RemarksPavan Kumar, Ph.D., Senior Scientist, Biomarkers and Personalized Medicine, Eisai

9:55 Identification of Urinary microRNA Biomarkers of Glomerular InjuryRounak Nassirpour, Ph.D., Principal Scientist, Investigative Pathology Laboratory, Drug Safety R&D, PfizerRecent studies have reported significant levels of microRNAs in a variety of body fluids, raising the possibility that microRNAs could serve as useful biomarkers. Here we describe urinary microRNA expression alterations in preclinical models of kidney injury. We describe microRNA changes in both the isolated glomeruli as well as the urine specimen from these established models of glomerular injury. The microRNAs identified may be promising preclinical urinary biomarkers for drug-induced glomerular injury.

10:20 MiRNAs as Circulating Biomarkers for Neurodegenerative DisordersPavan Kumar, Ph.D., Senior Scientist, Biomarkers and Personalized Medicine, EisaiA non-invasive and quantitative assay for early detection of Alzheimer’s disease (AD) is required to aid patient selection in clinical trials, monitor disease progression and early response to treatment, and to better plan patient clinical care. microRNAs have immense potential as biomarkers for clinical use because of their stability and ease of detection in most tissues, especially blood. Data will be presented on follow-up studies to our original 7-miRNA signature for AD diagnostics, including current activity in circulating miRNAs in the AD space.

10:45 MicroRNAs as Biomarkers in Clinical FluidsMartin Beaulieu, Ph.D., Director, MicroMarkers™, Regulus TherapeuticsmicroRNAs (miRs) are regulatory factors that function to repress the transcription of mRNA. Because each miR contains a seed sequence that is complementary to the UTR region of up to ~50 mRNA, the biological impact from the modulation of just a single miR can be significant. Expression profiles are deregulated in cells undergoing pathophysiologic stress suggesting potential as markers of disease states. miRs are ubiquitous and highly stable in the circulation due to the fact that they are short (~22 nt), protein bound and often travel encapsulated in microvesicles. Based on these favorable characteristics as biomarkers, we developed a miR profiling platform to discover new therapy response (predictive) and prognostic markers. Under the Regulus MicroMarkers™ division, Regulus has conducted large-scale profiling studies and has profiled over 3,000 clinical samples to date and has identified potential miR biomarkers for a variety of disease conditions. Recent results and new biological insights are planned to be presented.

11:10 MiRNAs as Biomarkers for Cancer Development and Drug ResistanceBing-Hua Jiang, Ph.D., Professor, Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityOur recent study demonstrates that a number of microRNAs (miRNAs) are downregulated in several kinds of human cancers including ovarian, breast, lung, colon and glioma; and that levels of miRNA suppression are associated with cancer development and drug resistance, and are involved in regulating tumor growth and angiogenesis. To understand the mechanism, we found that some miRNAs are inhibited by DNA methylation, while some miRNAs are inhibited by higher levels of reactive oxygen species (ROS) production in cancer cells.

11:35 Universal Screening Test Based on Analysis of Circulating Organ-Enriched microRNAsKira Sheinerman, Ph.D., CEO, DiamiR Biosciences Corp.Early detection is critical for effective treatment of neurodegenerative diseases, cancer and other pathologies, where disease progression frequently leads to irreversible changes in underlying pathophysiological processes. DiamiR has developed a novel framework for early detection of pathology in a particular organ system, organ or tissue based on analysis of circulating organ-enriched microRNAs, the Universal Screening Test (UST). Data on detection of pathologies in three organ systems - gastrointestinal, pulmonary, and neurological - will be presented. UST applications and ongoing and future studies will be discussed.

12:05 pm Luncheon Presentation: Identification and Validation of microRNA Biomarkers on the nCounter® Platform

Sponsored by

Lucas Dennis, Ph.D., Senior Scientist, NanoString TechnologiesMicroRNAs are implicated in the regulation of many biological processes and recent work has focused on investigating the promise of miRNA expression signatures as prognostic indicators of disease states. nCounter miRNA Expression assays enable users to rapidly, efficiently, and simultaneously profile >800 highly curated human miRNAs on the nCounter platform. These assays are compatible with total RNA isolated from any source. This unique targeted discovery and validation tool enables collection of expression data quickly with minimal handling, making it an ideal solution for both targeted biomarker discovery and validation.

microRNAs in Personalized Medicine1:30 Chairperson’s RemarksAjay Goel, Ph.D., Baylor Research Institute

1:35 Presentation to be Announced

2:00 Circulating miRNAs in Autoimmune Disorders – Opportunities as Biomarkers for Patient Stratification and ChallengesHungyun Lin, Ph.D., Principal Scientist, Drug Safety R&D, PfizerUnique miRNA expressions have been described in the intestinal epithelial cells and in the peripheral blood of Crohn’s disease (CD) patients. Selective miRNAs with important roles in regulating key pathogenesis in CD inflammation were assembled as an assay panel for screening of plasma from CD patients and healthy volunteers. The profile of a number of circulating miRNAs is capable of distinguishing CD patients from healthy volunteers. The results demonstrated the potential utility of circulating miRNAs as biomarkers for CD detection.


MARCH 16-17

2:25 MiRNA Biomarkers for Colorectal CancersAjay Goel, Ph.D., Director, Epigenetics and Cancer Prevention, Baylor Research InstitutemicroRNAs (or miRNAs) are emerging as important regulators of gene expression in cancer. Overexpression of specific miRNAs has been linked to the stepwise disease progression during the normal-adenoma-cancer sequence in colorectal cancer (CRC). Given their cancer-specific pattern of expression, remarkable stability and presence in blood and other body fluids, miRNAs are considered to be highly promising cancer biomarkers. Accumulating evidence firmly supports the existence of unique ‘miRNA signatures’ that can not only facilitate earlier detection of the tumor, but can also assist in predicting disease recurrence and therapeutic outcome to current treatment regimens.

2:50 Sponsored Presentation (Opportunity Available)

3:05 Refreshment Break in the Exhibit Hall with Poster Viewing

microRNA in Disease Diagnostics3:40 Chairperson’s RemarksDavid Henshall, Ph.D., Royal College of Surgeons in Ireland

3:45 Circulating miRNA Markers for Disease DiagnosisXuemei Zhao, Ph.D., Principal Scientist, Molecular Biomarkers and Diagnostics Laboratory, MerckThis presentation will cover: 1) circulating miRNAs hold great promise as disease diagnosis markers, and 2) a multiplexed RT-qPCR platform is utilized to identify a miRNA classifier for disease diagnosis.

4:10 MicroRNA Biofluid Profiles as Diagnostic Biomarkers in EpilepsyDavid Henshall, Ph.D., Professor, Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, IrelandEpilepsy is a common, serious neurological disorder characterized by recurring seizures that may result from often subtle brain injuries. There is a major unmet need for a molecular biomarker of epilepsy to assist prognosis, diagnosis and treatment decisions. Emerging data show brain-specific microRNAs exert potent effects on seizures but whether these molecules are suitable biomarkers is uncertain. Data will be presented from microRNA profiling of biofluids from epilepsy patients and experimental models which support the potential of microRNAs as diagnostic biomarkers in epilepsy.

4:35 Circulating microRNAs Show Promising Clinical Implications for Type 2 DiabetesElena Flowers, Ph.D., Assistant Professor, Physiological Nursing, University of California, San FranciscoType 2 diabetes is a pervasive public health problem that affects nearly 10% of the US population and is associated with increased mortality and healthcare costs. There is strong evidence that circulating microRNAs are prodromal biomarkers for risk for type 2 diabetes. Further, circulating microRNAs may be useful for predicting individual response to risk reduction interventions. Given these observations, microRNAs have the potential to meaningfully improve prevention, detection, and treatment of the type 2 diabetes epidemic.


5:15 Welcome Reception in the Exhibit Hall with Poster Viewing

6:15 Short Course RegistrationRecommended Dinner Short Course*6:30-9:30 (SC1) Systems Biology, Evidence Synthesis and in silico Discovery Approaches to microRNA Biomarkers*Separate registration required. See page 3 for details.

TUESDAY, MARCH 17

7:30 am Breakfast Roundtable DiscussionsRoundtable discussions are interactive, topic-specific discussions hosted by expert moderators and open to all attendees. These sessions provide a forum for discussing key issues:

• Topic 1: microRNA Normalization Strategy Moderator: Christos Argyropoulos, M.D., Ph.D., University of New Mexico School of Medicine

• Topic 2: Quantitation Issues Moderator: John Chevillet, Ph.D., Institute for Systems Biology

• Topic 3: Biomarker Biology: Delineating between Biomarkers that are the Drivers vs. Passengers in Disease Initiation, Progression and Maintenance Moderator: Andrea Kasinski, Ph.D., Purdue University

microRNA as Predictive Cancer Biomarkers8:15 Chairperson’s RemarksSubrata Sen, Ph.D., University of Texas MD Anderson Cancer Center

8:20 Talk Title to be AnnouncedFrank J. Slack, Ph.D., Director, Institute for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School

8:45 Tumor-Associated Circulating microRNAs as Biomarkers of Pancreatic CancerSubrata Sen, Ph.D., Professor and Deputy Chair, Translational Molecular Pathology, University of Texas MD Anderson Cancer CenterPancreatic cancer remains the fourth leading cause of cancer related death in the United States. Aberrantly expressing microRNAs (miRs) associated with deregulated genetic pathways contributing to the development of transformed cellular phenotypes have been reported in various human malignancies including pancreatic cancer. Varying levels of these aberrantly expressing tumor associated miRs have been detected in blood and body fluids of cancer patients. Our results indicate that tumor specific miRNA profiles in blood and body fluids can be developed as biomarkers of disease detection, prognosis and response to therapy for patients with pancreatic cancer.

9:10 MiRNAs as Predictors of Recurrence and Death in MelanomaIman Osman, M.D., Associate Director, NYU Cancer Institute & Professor, Oncology, and Director, NYU Interdisciplinary Melanoma Coop Group, New York University Langone Medical CenterIdentification of melanoma patients at the highest risk of recurrence remains a critical challenge. We recently reported our array-based discovery of prognostic serum miRNAs in melanoma. In this study, we show that 4 miRNAs (miR-150,30d, 15b, and 425) in combination with stage separated patients by recurrence-free survival and overall survival and improved prediction of recurrence over stage alone in both the training and validation cohorts (training RFS and OS, P < .001; validation RFS, P < .001; OS, P = .005). Our data demonstrate that serum miRNAs can improve melanoma patient stratification.

9:35 MicroRNAs that Control the PI3K Survival PathwayAndrei Thomas-Tikhonenko, Ph.D., Professor, Pathology and Laboratory Medicine, University of PennsylvaniaThe PI3K pathway plays a major role in both intrinsic cancer cell survival and its responses to chemotherapy. Members of this pathway are frequently affected by oncogenic mutations, PIK3CA and PTEN being prime examples. However, what controls this pathway in PIK3CA/PTEN non-mutated tumors is incompletely understood. Evidence will be presented that several microRNAs are major regulators of the PI3K pathway and that this regulation could be affected by single-nucleotide polymorphisms in the 3’ untranslated regions, making them potential biomarkers.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

microRNAs in Cancer Pathways10:40 Chairperson’s RemarksDavid S. Hong, M.D., University of Texas MD Anderson Cancer Center


MARCH 16-17

10:45 Epigenetic Regulation of miRNAs in a Human T Cell LeukemiaSundararajan Jayaraman, Ph.D., Clinical Associate Professor, Surgery, University of Illinois at ChicagoThe epigenetic regulation of non-protein coding miRNAs was determined in a T cell leukemia cell line, Jurkat following treatment with the histone deacetylase inhibitor, Trichostatin A (TSA). Global expression profiling of miRNAs revealed that in contrast to other tumors, TSA-mediated apoptosis in Jurkat cells was accompanied by an enhanced level of miR-494. Consistently, siRNA mediated silencing of miR-494 failed to block TSA-induced apoptosis. However, miR-494 knockout relieved TSA-mediated suppression of histone H2BE and poliovirus receptor related immunoglobulin domain containing gene (PVRIG), without affecting the level of non-protein coding nuclear paraspeckle assembly transcript (NEAT-1). These data provide significant insights into the role of miRNAs in T cell leukemias and identify novel targets for leukemia treatment.


11:25 A Combinatorial microRNA Therapeutics Approach to Eradicating Non-Small Cell Lung CancerAndrea Kasinski, Ph.D., Assistant Professor, Biological Sciences, Purdue UniversityStudies which have been instrumental in transitioning miRNA therapeutics into a clinical setting will be described including the successful attempts at treating the aggressive Kras;p53 NSCLC mouse tumor model. In this model we demonstrate the combined efficacy of two tumor-suppressive miRNAs, miR-34 and let-7. Half the dose of both miRNAs suppresses tumor growth leading to a survival advantage, without obvious toxicity. Clinical utility is reinforced through the use of a delivery vehicle already in clinical practice. This combinatorial miRNA therapeutic approach strikes numerous components of tumor-cell addictive pathways and highlights the ability to deliver multiple miRNAs in a safe and effective manner to the target lung tissue.

11:50 MicroRNA as Therapy – MRX34, a First-in-Human, First-in-Class microRNA Therapy in Advanced Cancer and Heme MalignanciesDavid S. Hong, M.D., Associate Professor and Chair, Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer CenterMRX34 is a liposome-formulated double-stranded mimic of the tumor suppressor microRNA-34 (miR-34). miR-34 functions in the p53 tumor suppressor pathway and regulates the expression of more than 20 cancer-related genes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-α, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also suppresses stem-like properties in cancer cells. Safety and preliminary efficacy data from 50 patients with hematologic malignancy or solid tumor enrolled in a Phase I clinical trial of MRX34 will be presented.

12:15 pm Close of Conference

Current Peer Research PostersPresent a Poster & Save!

Cambridge Healthtech Institute encourages attendees to gain further exposure by showcasing their current research in our dedicated poster sessions.

• Present your work to the leading pharmaceutical and academic researchers and scientists

• Gain exposure through the inclusion of your research abstract in conference materials

• Receive $50 off your registration fee

To secure a poster board and inclusion in the conference materials, your abstract must be submitted, approved and your registration paid in full by February 13, 2015.


Exosomes and Microvesicles as Biomarkers and DiagnosticsS E C O N D A N N U A L

MONDAY, MARCH 16

7:00 am Conference Registration and Morning Coffee

8:00 Welcome Remarks from Conference Director

Exosomal RNA/DNA in Cancer8:10 Chairperson’s Opening RemarksJanusz Rak, M.D., Ph.D., Jack Cole Chair in Pediatric Hematology/Oncology Professor of Pediatrics, McGill University, Montreal Children’s Hospital, RI MUHC

8:15 The Biology and Functional Contribution of Exosomes in Cancer Progression and MetastasisRaghu Kalluri, M.D., Ph.D., Professor and Chair, Cancer Biology, University of Texas MD Anderson Cancer Center

8:40 Exosomic microRNAs Affect the Biology of the Tumor MicroenvironmentMuller Fabbri, M.D., Ph.D., Assistant Professor, Pediatrics and Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine, Children’s Hospital Los AngelesmicroRNAs (miRNAs) are small non-coding RNAs which regulate the expression of about 30% of genes. miRNAs are secreted by cancer cells within exosomes, nanovesicles able to transfer intercellularly their content of DNA, RNA and proteins. We and others showed that specific exosomic miRNAs released by cancer cells can bind to receptors in surrounding cells and affect the biology of the tumor microenvironment. This lecture will highlight how interfering with this exosomic-miRNA-mediated cross-talk might lead to new anti-cancer treatments.


9:20 Networking Coffee Break

Exosome Profiling for Nucleic Acid and Protein Biomarkers

9:55 Oncogenic Cargo of Extracellular Vesicles – From DNA to Active ProteinJanusz Rak, M.D., Ph.D., Jack Cole Chair in Pediatric Hematology/Oncology Professor of Pediatrics, McGill University, Montreal Children’s Hospital, RI MUHCCancer cells shed extracellular vesicles (EVs) containing qualitatively altered, mutant molecular cargo. In this regard driver mutations are of special interest, as they possess a causative role in disease, exert transformation-like biological effects and reflect the genetic evolution of the underlying malignancy in real time. Oncogenic EV emission includes double-stranded DNA, transcripts and oncoproteins, while changes in the genome, transcriptome, proteome and phosphoproteome of EVs circulating in biofluids may reflect cancer progression and the effects of targeted anticancer agents.

10:20 Large-Scale Glycan and Lipid Profiling of Blood Exosomes from Human CancersRichard R. Drake, Ph.D., Professor and Director, Pharmacology, Medical University of South Carolina Proteomics CenterSeveral thousand serum and plasma samples from donors with colon and other cancers were used for rapid, bulk exosome/microvesicle precipitation by a commercial kit. The pellets were extracted in organic solvents to obtain lipid/glycolipid fractions or digested with peptide N-glycosidase to release N-linked glycans. Lipids and glycans were profiled on a high resolution 7T FTICR-MALDI mass spectrometer, generating hundreds of analyte signals per sample. Panels and individual species were assessed for their ability to stratify cancer from non-cancer samples.

10:45 Waste and/or Communication? Dissection of Subpopulations of Extracellular Microvesicles Deriving from Different Intracellular PathwaysNicole Meisner-Kober, Ph.D., Senior Investigator, RNA Biology, Developmental and Molecular Pathways, Novartis Institutes for Biomedical ResearchAfter their initial discovery in the early 1980s, exosomes had been primarily assigned a role in cellular waste disposal. Today it is well established that exosomes play an important role in cell-to-cell communication, both by direct contact as well as functional transfer of protein and RNA cargo. Here we report the dissection of different subpopulations of extracellular vesicles using single

molecule spectroscopy and imaging, and reveal that exosome samples comprise vesicle subpopulations originating from different intracellular biogenesis pathways, with differential surface markers, cargo and function specialized to either waste disposal or cellular communication, thereby reconciling these apparently opposing functions assigned to exosomes.

11:10 Redefining the Exosomal ProteomeAustin Yang, Ph.D., Associate Professor, Anatomy and Neurobiology, University of MarylandWe will present an integrated mass spectrometry and bioinformatics pipeline to unbiasedly define the “exosomal” proteome. By using various stable isotope quantitative proteomic approaches, we have carefully analyzed exosomal proteomes isolated from various sources and established a robust computational model to increase the sub-cellular resolution of exosomal proteomes. In particular, we will discuss our open source software package, IsoQuant, which provides a user friendly user interface to analyze exosomal proteomic datasets generated by various shotgun proteomic analyses.

11:35 D- and L-MARCKS-ED as Novel Exosome ProbesHang Hubert Yin, Ph.D., Associate Professor, Chemistry & Biochemistry and the BioFrontiers Institute, University of Colorado BoulderCurved membranes are a common and important attribute in exosomes and microvesicles. Our interest focuses on identifying and designing peptides that can sense membrane curvature based on established elements observed in natural curvature-sensing proteins. We have successfully identified a 25-mer peptide, MARCKS-ED, as well as its D-isomer that can both recognize PS with preferences for highly curved vesicles in a specific manner. These studies provide coveted specific probes for exosomes and microvesicles that may be of diagnostic and prognostic potential.

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

Potential of Exosomes as Biomarkers and Diagnostics1:30 Chairperson’s RemarksDavid T.W. Wong, D.M.D., DMSc, Professor and Associate Dean of Research, UCLA School of Dentistry; Director, Dental Research Institute

1:35 Salivary Exosome and Extracellular RNA: Biology and Translational UtilitiesDavid T.W. Wong, D.M.D., DMSc, Professor and Associate Dean of Research, UCLA School of Dentistry; Director, Dental Research InstituteUsing RNA-Seq, we have generated a comprehensive landscape of non-coding RNA (ncRNA) in human saliva. In a comparative analysis of >90 RNA-Seq data of different origins, we observed that piRNAs were surprisingly abundant in saliva compared to other bodily fluid or intracellular samples, which, nonetheless, resembled the level of piRNAs in embryonic stem cells and skin cells. In addition, to the best of our knowledge, we present the first global characterization and experimental validation of circRNAs in any type of extracellular bodily fluid.

2:00 Validation and Characterization of Endothelial Microvesicles in Sprague Dawley RatsSharon Sokolowski, Ph.D. Principal Scientist, Pfizer Global Research & DevelopmentMicrovesicles (0.5 – 1μM) in the peripheral blood of Sprague Dawley rats have been evaluated as potential biomarkers of vascular toxicity. Validation steps were completed to more fully characterize and understand the changes observed in peripheral blood microvesicle absolute counts in normal, dosed, and diseased animals. Taking into consideration the advantages and caveats of microvesicle evaluation, application of microvesicles as safety and efficacy biomarkers during drug development was explored.

2:25 Circulating Extracellular Vesicles as Possible New Biomarkers for Drug-Induced Liver InjuryQiang Shi, Ph.D., Visiting Scientist, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug AdministrationDrug induced liver injury (DILI) is the leading cause for acute liver injury, and a major reason for approved drugs being withdrawn from the market. Currently used DILI biomarkers lack organ specificity. Circulating extracellular vesicles (EVs) are being vigorously explored as a potential source of novel DILI biomarkers. EVs from both the blood and urine have been found to contain mRNAs, microRNAs or proteins that not only reflected liver injury per se, but also were indicative of DILI etiology.


MARCH 16-17



3:45 Non-Invasive Intracellular Kidney Biopsies: The Promise of Urine Exosomal BiomarkersPeter Yuen, Ph.D., Staff Scientist, Renal Diagnostics & Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthProximal fluid biomarkers can add organ specificity to circulating biomarkers. Exosomes, although a minor subfraction of urine, provide unique insights into kidney function because their biogenesis preserves cytoplasmic and plasma membrane information content from all epithelial cells along the nephron. Two types of exosomal biomarkers have emerged: a) functional markers (channels, transporters, and mRNA) that reflect the current functional state of the kidney, and b) decision-making molecules (transcription factors and miRNA) that predict the future status of kidney epithelial cells.

4:10 Extracellular Vesicles (EVs) as a Molecular Diagnostic PlatformClark C. Chen, M.D., Ph.D., Associate Professor and Chief, Stereotactic and Radiosurgery; Vice-Chairman, Academic Affairs, Neurosurgery, University of California, San DiegoExtracellular vesicles (EVs) are cell-secreted vesicles that range 30-2,000 nm in size. These vesicles are secreted by both normal and neoplastic cells. Physiologically, EVs serve multiple critical biologic functions, including cellular remodeling, intracellular communication, modulation of the tumor microenvironment, and regulation of immune function. Because EVs contain genetic and proteomic contents that reflect the cell of origin, it is possible to detect tumor-specific material in EVs secreted by cancer cells. Importantly, EVs secreted by cancer cells transgress anatomic compartments and can be detected in the blood, cerebrospinal fluid, and other bio-fluids of cancer patients. In this context, there is a growing interest in analyzing EVs from the bio-fluid of cancer patients as a means of disease diagnosis and therapeutic monitoring. This talk will focus on the development of EVs as a diagnostic platform for the most common form of brain cancer, glioblastoma, and discuss potential clinical translational opportunities.

4:35 Point-of-Care Diagnostic Technologies for Exosomal AnalysisHakho Lee, Ph.D., Assistant Professor, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical SchoolThis presentation will review the portable platforms that we have developed for exosome analysis. These include 1) in-flow filtration devices to enrich exosomes directly from biological fluids; 2) a nano-plasmonic chip to profile exosomal protein; and 3) microfluidic systems for on-chip RNA detection. Clinical applications of the developed platforms will also be discussed.


5:15 Welcome Reception in the Exhibit Hall with Poster Viewing

6:15 Short Course RegistrationRecommended Dinner Short Course*

6:30-9:30 (SC2) Executive ThinkTank: Development of Exosome-Based Diagnostics*Separate registration required. See page 3 for details.

TUESDAY, MARCH 17

7:30 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

Role of Exosomes in Cancer Mechanism and Cancer Biomarkers

8:15 Chairperson’s RemarksTheresa Whiteside, Ph.D., M.D.H.C., Professor, Pathology, Immunology & Otolaryngology, University of Pittsburgh Cancer Institute

8:20 Tumor-Derived Exosomes (TEX) as Biomarkers of Human Immune Cell Dysfunction and Tumor ProgressionTheresa Whiteside, Ph.D., M.D.H.C., Professor, Pathology, Immunology & Otolaryngology, University of Pittsburgh Cancer InstituteDysfunction of immune effector cells is common in human cancers and is linked to poor outcome. The magnitude and mechanisms responsible for dysfunction are tumor-growth dependent. TEX carry a molecular cargo that down-regulates anti-tumor activities of immune cells. Elevated plasma levels of TEX and their molecular/genetic profile serve as surrogate indicators of immune cell dysfunction and thus as prognostic non-invasive biomarkers in cancer.

8:45 Tumor Extracellular Vesicle-Induced Signaling in Recipient Cells: It’s All About the TumorMichael Graner, Ph.D., Associate Professor, Neurosurgery, University of Colorado School of MedicineExtracellular vesicles (EVs) are virus-sized membrane-enclosed particles released from cells into the extracellular milieu. EVs are compact information packets containing proteins, lipids, nucleic acid species, and other metabolites reflecting their cell of origin, but can also have dramatic impacts on cells that interact with EVs. We determined altered signaling pathways in recipient cells (tumor and “normal” cells) upon encounter with glioma EVs. Generally, tumor signaling pathways trend towards aggression, while pathways in other cells result in entities that also benefit the tumor.

9:10 Circulatory Exosomal Cargo as Biomarkers of Recurrent Lung TumorsRadha Munagala, Ph.D., Assistant Professor, Department of Medicine, James Graham Brown Cancer Center, University of LouisvillePoor outcomes and relapse in non-small cell lung cancer patients indicate the need for new screening and biomarkers for early detection. We examined circulatory serum exosomes from primary and recurrent lung tumor-bearing mice and noted distinct exosomal protein markers and miRNA profile. In addition, unique recurrence associated miRNAs were observed in exosomes from recurrent compared to primary tumor mice. The data suggest that the circulatory exosomes can be a true representation of tumor-profile and have significant biomarker potential.

9:35 Exosomes as Mediators of JAK/Stat Activation-Regulation of MetastasisJacqueline Bromberg, M.D., Ph.D., Physician-Scientist, Breast Cancer, Memorial Sloan-Kettering Cancer CenterTumors constitutively release membrane-derived nano-vesicles or exosomes (TDExo) that are readily detected in body fluids and have been found to play important roles in signaling, immunomodulation and metastasis. In examining the molecular mediators of the cross-talk between tumor exosomes and the host, our preliminary and published work identifies the pro-inflammatory cytokine IL6/JAK/Stat3 axis not only in local tumor:stoma cross-talk but also as a critical and targetable contributor to the metastatic inductive properties of TDExos.


Exosomes as Disease Biomarkers10:45 LRRK2 and Other Novel Exosome Proteins in Parkinson’s DiseaseAndrew West, Ph.D., John A. and Ruth R. Jurenko Professor of Neurology; Associate Professor, Neurology and Neurobiology; Co-Director, Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham

11:10 Novel Role of Microvesicles in Cardiovascular and Autoimmune DiseasesMing-Lin Liu, M.D., Ph.D., Research Assistant Professor, Dermatology, Perelman School of Medicine, University of PennsylvaniaMicrovesicles are small membrane vesicles released from different cell types in various human diseases. Microvesicles have been detected in the circulation and in human tissues. These microvesicles may carry bioactive molecules including lipids, proteins or nucleic acids, and contribute to the development of cardiovascular disease and autoimmune inflammation. The changes in number and composition of microvesicles may reflect the pathophysiological conditions of human diseases. Therefore, detection of microvesicles may serve as potential biomarkers for diagnostic and prognostic use.

11:35 Extracellular Vesicles in Pulmonary Vascular Disease – Friend or Foe?Jason Aliotta, M.D., Assistant Professor, Medicine, Warren Alpert Medical School, Brown UniversityPulmonary arterial hypertension is a disease that is characterized by pulmonary vascular remodeling resulting in right ventricular failure and death. We have found that extracellular vesicles (EVs) isolated from mice with monocrotaline-induced pulmonary hypertension induce features of this disease when injected into normal mice. In addition, EVs isolated from mesenchymal stem cells can reverse this disease phenotype. Our hope is that these studies may someday aid in the development of new strategies to treat this lethal disease.

12:00 pm Close of Conference


Long Non-Coding RNA in CancerI N A U G U R A L

TUESDAY, MARCH 17

12:00 pm Conference Registration

Long ncRNA as Cancer Biomarkers1:30 Chairperson’s Opening RemarksJingfang Ju, Ph.D., Associate Professor and Co-Director, Translational Research, Pathology, Stony Brook University

1:35 Non-Coding RNAs in CancerCarlo M. Croce, M.D., Distinguished University Professor, The John W. Wolfe Chair in Human Cancer Genetics, Director, Genetics Institute, The Ohio State University

2:00 Clinical Significance of Long Intergenic Non-Coding RNA-p21 in Colorectal CancerJingfang Ju, Ph.D., Associate Professor and Co-Director, Translational Research, Pathology, Stony Brook UniversityTumor suppressor p53 regulates a number of non-coding RNAs. We quantified the expression of lincRNA-p21 in colorectal cancer patients. The expression level of lincRNA-p21 was significantly lower in CRC tumor tissue. Rectum tumors showed a higher level of lincRNA-p21 than tumors in the colon. In addition, lincRNA-p21 was significantly higher in stage III than stage I tumors. Elevated levels of lincRNA-p21 were significantly associated with vascular invasion. These results suggest that lincRNA-p21 may contribute to CRC disease progression.

2:25 PCAT18 as a Novel Biomarker and Therapeutic Target in Prostate CancerCheryl Helgason, Ph.D., Senior Scientist, Experimental Therapeutics, BC Cancer Research CenterWe utilized RNA sequencing to identify lncRNAs differentially expressed in metastatic prostate cancer (PCa), an incurable disease. PCAT18, the most highly up-regulated transcript, is prostate and PCa specific. It is detectable in plasma and able to discriminate localized versus metastatic PCa. Functional studies demonstrate a specific role in blocking PCa cell proliferation, invasion and migration. These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa. Additional studies have identified a potential oncosuppressive lncRNA with prognostic significance.



Role of lncRNA in Cancer Progression4:10 Chairperson’s RemarksRichard I. Gregory, Ph.D., Associate Professor, Biological Chemistry and Molecular Pharmacology, Children’s Hospital Boston, Harvard Stem Cell Institute (HSCI), Harvard Medical School

4:15 Targeting lncRNA in Ovarian CancerAnil K. Sood, M.D., Professor and Vice Chairman, Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center

4:40 Role of Long Non-Coding RNAs in microRNA Regulation and CancerRichard I. Gregory, Ph.D., Associate Professor, Biological Chemistry and Molecular Pharmacology, Children’s Hospital Boston, Harvard Stem Cell Institute (HSCI), Harvard Medical SchoolIt is emerging that long non-coding RNAs (lncRNAs) can have important roles in gene regulation. Dysregulation of these pathways is associated with cancer. We are investigating the role of lncRNAs in stem cell biology and cancer with a particular focus on how lncRNAs impact microRNA expression and function. Our most recent progress in this area will be presented.

5:05 A lincRNA Locus Associated with Metastatic MelanomaLaurent Lessard, Ph.D., Assistant Professor, Molecular Oncology, John Wayne Cancer InstituteIn a search for novel melanoma-associated lincRNA genes, we identified the CASC15 locus as a frequently gained and actively transcribed lincRNA domain in melanoma tumors. This talk will describe the molecular characterization, biomarker utility, and functional significance of CASC15 in metastatic melanoma progression.

5:30 Close of Day


6:00-9:00 (SC3) RNA-Seq: A Fundamental Guide to the Field*Separate registration required. See page 3 for details.

WEDNESDAY, MARCH 18


Linking lncRNAs to Cancer8:00 Chairperson’s RemarksMyriam Gorospe, Ph.D., Senior Investigator, Laboratory of Genetics, National Institute on Aging-Intramural Research Program, National Institutes of Health

8:05 Senescence LncRNPsMyriam Gorospe, Ph.D., Senior Investigator, Laboratory of Genetics, National Institute on Aging-Intramural Research Program, National Institutes of HealthSenescent cells accumulate in aging tissues, and their metabolic and gene expression profiles are linked to many age-related pathologies including cancer. I discuss our recent studies on the expression patterns and functions of senescence-associated long noncoding RNAs (lncRNAs), focusing on three lncRNAs differentially expressed with senescence: LincRNA-p21 (Mol Cell, 2012) which suppresses translation of select mRNAs, HOTAIR (Nat Commun, 2013), which promotes ubiquitin-mediated proteolysis of select proteins, and 7SL (Nuc Acids Res, 2014) which suppresses p53 translation.

8:30 LncRNA PVT1 Augments MYC in Human CancersAnindya Bagchi, Ph.D., Assistant Professor, Masonic Cancer Center, University of MinnesotaIn cancers with 8q24 gain, a common mutation found in almost all human cancers, MYC is co-gained with adjacent lncRNA PVT1. We recently showed that PVT1 augments MYC in these cancers. In this lecture I will discuss the possibility of exploiting lncRNA PVT1 as a surrogate target for MYC, an otherwise undruggable cancer gene in human cancers.

8:55 Long Non-Coding RNA as Regulator of Aggressive Prostate CancerDimple Chakravarty, Ph.D., Assistant Professor, Pathology, Weill Cornell Medical CollegeLncRNAs comprise a heterogeneous group of non-coding transcripts (>200 nt) that have emerged as key mediators of cellular homeostasis. Some lncRNAs like NEAT1 have evolved to achieve functional specialization. Our ongoing studies indicate that NEAT1 nucleates with cellular proteins to regulate fundamental like transcription and DDR. NEAT1 functions as a driver of prostate cancer progression and therapy resistance. Using a combination of next-generation sequencing and biochemical methods our studies will explain the intricate molecular mechanisms that link DDR to oncogenic modulation.



Functional Characterization of lncRNAs10:30 Chairperson’s RemarksAlexander Pertsemlidis, Ph.D., Associate Professor, Pediatrics and Cellular & Structural Biology, University of Texas Health Science Center at San Antonio

10:35 The Pivotal Role of the Oncofetal H19 lncRNA in Human CancerAbraham Hochberg, Ph.D., Professor, Biological Chemistry, Hebrew University of Jerusalem; Co-Founder and CSO, BioCancellImad Matouk, Ph.D., Senior Researcher, Laboratory of Abraham Hochberg, Hebrew University of JerusalemThe imprinted H19 gene transcribes an onco-fetal lncRNA that is essential for human tumor growth. H19 is highly expressed in embryogenesis and cancer and serves as a precursor for miR-675. H19 is induced by hypoxic stress in a p53-dependent manner. Furthermore, numerous EMT inducers also induced H19/miR-


MARCH 17-18

675 expression to enhance metastasis. H19 is involved in multi-drug resistance and possesses both diagnostic and prognostic values. All of these highlight the importance of developing DNA-based therapy centered on a lncRNA system. We have successfully used regulatory elements of H19 for the treatment of bladder, ovarian, and pancreatic cancers and liver metastases in clinical trials.

11:00 Antisense Oligonucleotides for Regulation of Long Non-Coding RNASusan Freier, Ph.D., Vice President and Distinguished Research Fellow, Isis PharmaceuticalsLarge scale evaluation of RNA expression continues to identify an increasing number of long non-coding RNAs (lncRNA) expressed in mammalian systems. Antisense oligonucleotides (ASO) provide a straightforward method for determining function for these RNAs by specific ASO-mediated targeted degradation of the lncRNA in vitro or in vivo. MALAT1 is a ubiquitous, highly expressed, nuclear retained lncRNA with a demonstrated role in lung cancer metastasis. ASO-mediated depletion of tumor MALAT1 levels has been shown to prevent primary tumor metastasis after tumor implantation. The use of ASOs to evaluate the roles of MALAT1 and other lncRNAs in vivo will be presented.

11:25 Using ncRNAs to Identify Cancer Cell VulnerabilitiesAlexander Pertsemlidis, Ph.D., Associate Professor, Pediatrics and Cellular & Structural Biology, University of Texas Health Science Center at San AntonioIn an unbiased and comprehensive approach, we have combined a high-throughput screening platform with libraries of inhibitors of short and long non-coding RNAs. We use this platform to identify ncRNAs that reduce cell viability in general, and those that specifically sensitize cells to microtubule-targeting agents. Regulatory targets of candidate ncRNAs are identified and the response of cancer cells to perturbations in candidate ncRNA levels are assessed through a combination of in vitro, in silico and in vivo approaches.

11:50 Functional Characterization of Long Non-Coding RNAs in the p53 Tumor Suppressor PathwayNadya Dimitrova, Ph.D., Postdoctoral Fellow, Laboratory of Tyler Jacks, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyWe are studying long non-coding RNAs (lncRNAs) that are directly regulated by the transcription factor p53. Using the mouse as a model organism, we have developed genetic tools to address the contribution of p53-regulated lncRNAs to this important tumor suppressor pathway. Our findings indicate a key role for lncRNAs in the transcriptional control of proteins downstream of p53 and reveal an unanticipated layer of regulation in the p53 tumor suppressor network.

12:15 pm Luncheon Co-Presentation: The Use of LncRNA Regulatory Elements for Innovative Anticancer Therapy; Oncofetal H19: Mechanism, Clinical Applications and Future Development

Sponsored by

Mark L. Tykocinski, M.D., Scientific Advisory Board, BioCancellMichal Gilon, Ph.D., Vice President, R&D, BioCancellThe H19 long-non-coding-RNA gene, highly and specifically expressed in a wide spectrum of tumors, is the ideal basis for highly selective anti-cancer therapy. Using the H19 regulatory elements to drive the expression of Diphtheria toxin, we have created a cancer-targeted DNA-based killing drug that leaves the healthy surrounding tissues unharmed. Our talk will review H19 mechanism of action, the creation of a “ killing chromosome “ that combines H19 and IGF2 regulatory elements, and our promising clinical findings, which have lead us towards phase III clinical trial in bladder cancer.

Epigenetic Mechanisms1:30 pm Chairperson’s RemarksSubhrangsu S. Mandal, Ph.D., Associate Professor, Chemistry & Biochemistry, University of Texas Arlington

1:35 Endocrine Regulation and Disruption of Non-Coding RNAsSubhrangsu S. Mandal, Ph.D., Associate Professor, Chemistry & Biochemistry, University of Texas ArlingtonNon-coding RNAs are emerging players in regulation of gene expression and chromatin dynamics and their misregulations are associated with a variety of human diseases including cancer. Studies from our laboratory demonstrate that long non-coding RNAs (lncRNAs) are transcriptionally regulated by steroid hormones such as estrogen and potentially disrupted upon exposure to estrogenic endocrine disrupting chemicals. Here we will present our recent findings on the epigenetic mechanism of endocrine regulation and disruption of selected lncRNA in vitro and in vivo and their roles in tumorigenesis.

2:00 LncRNAs in Epigenetic RegulationMamta Gupta, Ph.D., Assistant Professor, Medicine, Mayo Clinic

2:25 Epigenetic Regulation of the Human Genome by lincRNAsAhmad M. Khalil, Ph.D., Assistant Professor, Genetics and Genome Sciences, Case Western Reserve University School of MedicineIt is now estimated that the human genome encodes over 8,000 long intergenic non-coding RNAs (lincRNAs), but the biological functions of only a few lincRNAs have been elucidated to date. We have utilized state-of-the-art transcriptomic approaches both in vitro and in vivo to identify lincRNAs that are deregulated in several cancer types, with the hope of identifying tumor-suppressor and oncogenic lincRNAs. Subsequent functional studies are providing insights into the role of these lincRNAs in cancer initiation, progression and metastasis.

2:50 Selectively Activating Gene Expression by Targeting Long Non-Coding RNACaroline J. Woo, Ph.D., Scientist, RaNA TherapeuticsLong non-coding RNAs (lncRNA) can regulate transcription by recruiting epigenetic modifying complexes to target genes. PRC2, an epigenetic transcriptional repressor complex, is recruited to its target gene, via a specific lncRNA, to inhibit gene expression. We use synthetic oligonucleotides to selectively block PRC2 binding to a specific lncRNA, thereby de-repressing the expression of an mRNA, and resulting in increased amounts of the therapeutic protein.

3:15 Close of Conference


Extracellular RNA in Drug and Diagnostic DevelopmentI N A U G U R A L

TUESDAY, MARCH 17

12:00 pm Conference Registration

Sequencing and Profiling Strategies for Extracellular RNA Analysis

1:30 Chairperson’s Opening RemarksAleksandar Milosavljevic, Ph.D., Professor, Molecular and Human Genetics, Baylor College of Medicine

1:35 The Rat microRNA Body Atlas: Towards Understanding Serum microRNA Changes and Their Utilization as Biomarkers of Specific Organ ToxicityAaron Smith, Senior Toxicologist, Investigative Toxicology, Lilly Research LaboratoriesmicroRNAs (miRs) have many attributes which have elicited considerable interest in their use as serum-based biomarkers of organ injury. In order to identify tissue specific/enriched miRs and to understand serum miR changes, we have constructed a rat miR body atlas using Illumina miR sequencing of 22 rat tissues of toxicologic interest. These data provide a valuable miR platform to identify serum miR changes reflecting their organ-specific origin during injury to the liver and pancreas in vivo.

2:00 MicroRNA Biomarkers Circulate in Multiple Biophysical States: Implications for Diagnostics DevelopmentJohn Chevillet, Ph.D., Postdoctoral Research Fellow, Laboratory of Leroy Hood, Institute for Systems BiologyCirculating microRNAs have been reported to exist in multiple biophysical states, including most famously as cargo of 50-100 nm extracellular vesicles known as exosomes. Our understanding of circulating miRNA biomarkers is rapidly evolving and the development of sensitive, accurate and precise analytic approaches can be substantially assisted by a quantitative understanding of their distribution in physical and biochemical fractions of patient specimens.

2:25 Picoliter Droplet-Based Digital PCR and microRNA QuantificationValerie Taly, Ph.D., Group leader, CNRS researcher, University Paris-DescartesDroplet-based microfluidics has led to the development of highly powerful systems that represent a new paradigm in high-throughput screening where individual assays are compartmentalized within microdroplet microreactors. In particular, picoliter droplet-based digital PCR has recently demonstrated its pertinence to perform millions of single molecule reactions in parallel for the detection and quantification of cancer genetic markers. We will present the development and validation of this new technology for the multiplex detection of clinically relevant microRNA.



Extracellular RNA Analysis and Toxicity Biomarkers4:10 Chairperson’s RemarksMatthew Roth, Ph.D., Assistant Professor & Co-Director, Bioinformatics Research Lab, Baylor College of Medicine; Data Management & Resource Repository of the Extracellular RNA Consortium (NIH)

4:15 Evaluation of Circulating microRNAs as Biomarkers of Toxicity in Drug DiscoveryTatiana Sharapova, Ph.D., Scientist I, Cellular and Molecular Biology, AbbVieAt AbbVie we conducted investigations designed to evaluate the potential utility of circulating miRNAs as biomarkers of drug induced toxicity in various tissues including testicular, pancreatic, renal and liver injuries. Altogether, the data indicate that serum and/or urinary miRNAs could have utility as biomarkers of toxicity and support the future development of multiplexed panels of miRNAs to monitor multiple toxic changes from a single sample.

4:40 Potential of Extracellular microRNAs as Biomarkers of Acetaminophen Toxicity in ChildrenXi Yang, Ph.D., Research Biologist, Systems Biology, FDA/National Center for Toxicological ResearchRecent studies of adults with acetaminophen (APAP) -induced liver injury have

reported human serum microRNA-122 (miR-122) as a novel biomarker. The goal of this study was to examine blood and urine extracellular miRNAs as potential biomarkers for APAP liver injury in children. Our results demonstrate that urinary extracellular miRNAs (miR-375) have the potential to be used as biomarkers in children to detect APAP-induced hepatotoxicity in clinical practice.

5:05 Quantitative PCR Profiling for Selection of Candidate microRNA Kidney Damage MarkersMira Pavkovic, Ph.D., Bayer Pharma AG, GDD-GED-Toxicology; currently Postdoctoral Fellow, Systems Pharmacology, HarvardExtracellular microRNAs (miRNAs) have emerged as novel biomarkers (BMs) for various pathological states. Issues like low miRNA content in biofluids and questions concerning normalization strategies represent clear challenges in terms of detection methods and analysis workflows. To evaluate these issues for urinary miRNAs we performed rat studies with two differently acting nephrotoxicants and developed a possible analysis approach for selection of BM candidates from profiling data of urinary miRNAs using PCR.

5:30 Close of Day


6:00-9:00 (SC4): Circulating Nucleic Acid Biomarkers for Development of Non-Invasive Prenatal Tests*Separate registration required. See page 3 for details.

WEDNESDAY, MARCH 18


Challenges in Biomarker Applications of Circulating RNA

8:00 Chairperson’s RemarksSaumya Das, M.D., Ph.D., Assistant Professor, Medicine, Harvard Medical School

8:05 Bioinformatics ChallengesAleksandar Milosavljevic, Ph.D., Professor, Molecular and Human Genetics, Baylor College of Medicine

8:30 Important Considerations for exRNA Biomarker DiscoveryLouise C. Laurent, M.D., Ph.D., Assistant Professor, Reproductive Medicine, University of California San Diego Health ScienceThis presentation will cover work and lessons learned from the NIH External RNA Communication Consortium (ERCC) Sample and Assays Working Group.

8:55 Panel Discussion: Standardization Issues for Extracellular RNA ResearchModerator: 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)Panelists:Louise C. Laurent, M.D., Ph.D., Assistant Professor, Reproductive Medicine, University of California San Diego Health ScienceTatiana Sharapova, Ph.D., Scientist I, Cellular and Molecular Biology, AbbVieAaron Smith, Senior Toxicologist, Department of Investigative Toxicology, Lilly Research LaboratoriesScott J. Tebbutt, Ph.D., Associate Professor, University of British Columbia, & CSO, PROOF Centre of Excellence, Vancouver, CanadaXi Yang, Ph.D., Research Biologist, Systems Biology, FDA/National Center for Toxicological Research• RNA isolation and quantification challenges• Bioinformatics challenges unique to exRNA data• Microarrays v. qPCR v. RNA-Seq• Unique advantages of exRNA biomarkers• Rate limiting steps for progress in biomarker applications




Long Non-Coding Extracellular RNA Biomarkers10:30 Chairperson’s RemarksRichard P. Kraig, M.D., Ph.D., Professor, Neurology, The University of Chicago Medical Center

10:35 Extracellular, Long Non-Coding RNA Markers for Lung CancerLynn Hlatky, Ph.D., Professor, Medicine, and Director of Cancer Systems Biology, Tufts University

11:00 Circulating Ang2mRNA as a Prognostic Marker for Lung CancerAna Coelho, Ph.D., Professor, Oncology, Portuguese Oncology InstituteLung cancer remains a disease with a dismal prognosis. The development of prognostic markers would allow patients the choice of more aggressive and prolonged therapies. Circulating prognostic markers, such as mRNA levels, are practical tools, since peripheral blood samples are easy to obtain, not relying on the availability of adequate biopsy specimen. Moreover, circulating Ang-2 mRNA levels could help in the stratification of NSCLC patients and can easily be included in the design of preclinical studies.

11:25 PCA3: A Non-Invasive, Long Non-Coding RNA Marker of Prostate CancerGerald W. Verhaegh, Ph.D., Senior Scientist, Laboratory of Jack Schalken, Department of Experimental Urology, Radboud University Medical CenterThe PCA3 gene, encoding a long non-coding RNA, is over-expressed by prostate cancer cells in comparison with all other cells studied. The differential expression is great, permitting detection of the RNA in cancer cells shed into the urine after attentive digital rectal exam. Urinary PCA3 appears useful as a highly specific marker for prostate cancer.

11:50 Luncheon Presentation (Sponsored Opportunity Available) or Lunch on Your Own

Functional and Diagnostic Roles for Extracellular RNA1:30 pm Chairperson’s RemarksXi Yang, Ph.D., Research Biologist, Systems Biology, FDA/National Center for Toxicological Research

1:35 Exosomes and miR-219 in MS Myelination and MigraineRichard P. Kraig, M.D., Ph.D., Professor, Neurology, The University of Chicago Medical CenterMultiple sclerosis (MS) and migraine are clinically correlated. Work from our laboratory establishes a pathophysiological link involving myelin disruption between these disorders. Importantly, we discovered that environment enrichment (increased social, physical and creative activity) prompts release of microRNA-containing exosomes from blood that promote myelination. These nutritive exosomes can be harvested from dendritic cells grown in vitro. We are developing microRNA-containing exosomes that emulate environmental enrichment as a scalable therapeutic against brain demyelination including that seen from MS and migraine.

2:00 A Functional Role for Extracellular RNAs in Cardiac RemodelingSaumya Das, M.D., Ph.D., Assistant Professor, Medicine, Harvard Medical SchoolAs mortality from acute myocardial infarctions has decreased, its sequelae, heart failure and sudden cardiac death, have contributed significantly to disease burden. Novel insights into cardiac remodeling that follows the initial stress would provide novel biomarkers and therapeutic targets for cardiac remodeling. Here we describe our efforts to identify extracellular RNA biomarkers associated with cardiac remodeling using a microarray and an RNA-seq platform, and examine the possible functional role of selected ex-RNAs in disease pathogenesis.

2:25 Towards Establishing Blood-Based, RNA Diagnostics for Acute Heart Failure RecoveryScott J. Tebbutt, Ph.D., Associate Professor, University of British Columbia, & CSO, PROOF Centre of Excellence, Vancouver, CanadaSevere inotrope-dependent acute heart failure (AHF) is associated with poor clinical outcomes. There are currently no well-defined biomarkers of response to treatment that can be used to guide treatment or evaluate recovery in this patient population. In the present study, we are characterizing microRNAs as novel and emerging tissue and circulating biomarkers of HF in patients with severe inotrope-dependent AHF over the first 30 days of medical management or mechanical circulatory support (MCS).

2:50 Extracellular RNAs as Diagnostic Biomarkers of Cardiovascular DiseaseYigal Pinto, Ph.D., Professor, Cardiology and The Heart Failure Research Center, Academic Medical Center, NetherlandsBiomarkers have profoundly changed cardiology. By measuring circulating heart-specific proteins, diagnosis and management of the most important cardiac syndromes have dramatically changed. The next frontier is to combine different biomarkers into so-called multi-marker panels. Small RNAs like microRNAs are measurable in the circulation. This holds great promise as technologies emerge that allow us to measure with great accuracy multiple microRNAs together with standard protein biomarkers. This is expected to again redefine some major diagnostic and therapeutic areas in cardiology.

3:15 Close of Conference

MARCH 17-18

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microRNA as Biomarkers and Diagnostics Long Non-Coding RNA in Cancer

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