4th Annual RNA Interference June 19-21, 2006 - Lyophilization Conferences 2006

4th Annual RNA Interference June 19-21, 2006
San Francisco, CA
9:00-9:15 Chairperson?s Opening Remarks
Dr. Michael T. McManus, Assistant Professor, Department of Microbiology and Immunology, UCSF Diabetes Center, University of California, San Francisco
9:15-9:45 Lessons from the microRNA - Chronic Lymphocytic Leukemia Connection: New Paradigms in Molecular Oncology
Dr. George Calin, Research Assistant Professor, Molecular Virology, Immunology & Medical Genetics Department, Ohio State University
A critical question about cancer pathogenesis is how big is the impact of non-coding genes for both initiation and progression of the malignant phenotype. The ?classical? molecular oncology paradigm was that cancer is a genetic disease involving tumor-suppressor and oncogenic proteins. Recent findings that non-coding RNAs names microRNAs are involved in the pathogenesis of the majority of analyzed cancers reveals a new layer of complexity in the molecular architecture of human cancers.
9:45-10:15 microRNAs as Novel Targets for Cancer Therapy
Dr. C. Frank Bennett, Senior Vice President, Research, Isis Pharmaceuticals
MicroRNAs are small noncoding RNAs that regulate gene expression by inhibiting translation of the targeted RNAs. They can be thought of as naturally occurring antisense oligonucleotides. Although the mechanisms by which microRNAs block translation are not well characterized they have been documented to both promote degradation of the targeted RNA and block translation without causing changes in the level of the mRNA. Numerous studies have recently shown that marked changes in expression of micro-RNAs occur in a variety of malignancies and that these changes appear to contribute to the malignant phenotype. We have developed chemically modified oligonucleotides to either inhibit the function of microRNAs, thus promoting upregulation of microRNAs targeted genes or mimic the function of microRNAs, thus replacing the function of a microRNAs dysregulated in cancer cells. We have demonstrated that both strategies work well in cell culture based experiments. In addition, we have demonstrated that we can inhibit the function of microRNAs in multiple adult animal tissues by use of chemically modified antisense oligonucleotides.
10:35-11:05 microRNAs in Cancer and Development
Dr. Aurora Esquela Kerscher, Postdoctoral Fellow, Frank Slack Lab, Department of Molecular, Cellular & Developmental Biology, Yale University
In C. elegans, the let-7 microRNA controls the timing of seam cell terminal differentiation during epidermal cell development. However, in let-7 mutant animals, cells frequently fail to terminally differentiate, and instead elect to divide again, a hallmark of cancer. We devised a bioinformatic screen using rules developed from known let-7 target genes, to successfully identify numerous let-7 downstream targets, which we subsequently validated. For example, we found that let-7 targets let-60, the nematode Ras gene. let-7 is conserved in humans, where it has been linked to cancer. Specifically, human let-7 is poorly expressed or deleted in lung cancer, and over-expression of let-7 in lung cancer cells inhibits their growth, demonstrating a role for let-7 as a tumor suppressor gene in lung tissue. We have also shown that human let-7 is expressed in the developing mammalian lung and regulates the expression of important oncogenes implicated in lung cancer, including RAS, MYC and BCL-2. We found that human HRAS, KRAS and NRAS 3?UTRs contain multiple let-7 complementary sites, and that let-7 regulates RAS expression through these 3?UTRs, suggesting conservation of gene interactions and a mechanism for let-7?s involvement in cancer. We are currently investigating the role of let-7 and other oncomirs in regulating proto-oncogene expression during development and cancer, and on using miRNAs to suppress tumorigenesis.
11:05-11:35 microRNAs-Based Diagnostics in Cancer ? A New Approach
Prof. Zvi Bentwich, Chief Scientist, Rosetta Genomics LTD
MicroRNAs (mirs) are short non-coding RNAs recently recognized as central regulators of gene expression through post-transcriptional suppression. They play a major role in normal tissue development and differentiation, as well as in cancer and other diseases. Rosetta Genomics has developed an integrative approach combining bioinformatic predictions with microarray analysis and sequence-directed cloning, which led to the discovery and validation of over 200 novel human miRNAs, and to several hundreds of additional predicted mirs. Based on this large platform of miRNAs, and improved technology for mir detection, we are developing novel diagnostic tests for a number of major human cancers, encompassing both early detection, disease stratification and response to treatment. We will present our most updated results at the workshop, discussing the different patterns of miRNA expression in a number of human cancers.
1:00-1:30 miRNAs as Diagnostic Analytes and Therapeutic Intervention Points
Mr. David Brown, Director of Discovery, Asuragen, Inc.
We have used a combination of miRNA expression analysis in normal and cancer tissues and miRNA functional analysis in cultured cells to identify miRNAs whose mis-expression can affect gene pathways and cellular processes that can contribute to the development and progression cancer. Many of these miRNAs are being evaluated as analytes for diagnostic assays and as targets for therapeutic development. Examples of both applications will be presented.
1:30-2:00 Oncogenic microRNAs: The Gentle Balance between Development and Disease
Dr. J. Michael Thomson, Postdoctoral Research Associate, The Hammond Lab, Department of Cell & Developmental Biology, College of Medicine, University of North Carolina
MicroRNAs have surged to the forefront of molecular biology and genetics having been shown to regulate a wide array of biological functions, ranging from cell cycle to cell fate. More recently, microRNAs have been implicated in several human diseases, most notably, cancer. To better understand how they function, our lab has focused on expression profiling by microarrays. To this end, we have uncovered an interestingly conserved family of microRNAs, which participate not only in early embryonic development, but have been implicated in several human cancers. Ectopic expression of this microRNA cluster in hematopoietic stem cells accelerates tumor formation in a mouse model of Burkitt?s lymphoma and demonstrates the potential of non-coding RNAs to act as oncogenes. Our current focus has been on the upstream mitotic signaling and biological targets of this cluster of microRNAs. These and other issues related to oncogenic microRNAs will be discussed.
2:00-2:30 microRNA Profiling using qPCR Arrays
Dr. Chris Raymond, Research Fellow, Merck Research Laboratories
We have described a simple, robust, and sensitive method for microRNA detection (Raymond et al., RNA 11:1737) and have developed a profiling platform that includes 222 human and 197 mouse microRNAs. By employing laboratory automation, we have ramped up our profiling capacity to accommodate several hundred biologically interesting samples. Our core focus has been to generate an ?atlas? of profiles for normal tissues and for frequently used cell lines. We are in the process of profiling interesting disease-state tissues and determining if useful correlations between microRNA profiles and known phenotypes and clinical outcomes can be identified.
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