Academic Screening Workshop 2013 Agenda

Welcome and Registration

Expanding Landscape of Protein-Protein Interaction Networks in Cancer
Haian Fu, Professor and Director, Emory University, United States of America

The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer. Because of their critical roles in transmitting physiological and pathological signals, the once “undruggable” PPIs have emerged as a viable class of molecular targets for therapeutic interventions. This lecture will highlight Emory Center’s recent efforts in interrogating cancer genomics for cancer target discovery through a high throughput systems biology approach.

Pathways vs. Targets: Novel Therapeutic Approach to Fibrosis
Richard Neubig, Professor and Chair, Michigan State University, United States of America

Drug discovery usually starts with a molecular target but complex diseases may not readily suggest a viable target. We describe a Rho/SRF pathway reporter screen identifying novel compounds active in human scleroderma dermal fibroblasts without a known molecular target.

Making Cell-Based Assays Robust for High Throughput Drug Discovery – Adaptation to Antivirals
Roland Wolkowicz, Associate Professor, San Diego State University, United States of America

Genetic engineering through retroviral technology was used to develop mammalian cell-based assays for the monitoring of proteolytic events in the viral life cycle of HIV-1 and Flaviviridae. The assays are robust and multiplexed, making them ideal for high throughput screening. 

A Versatile, Bar-Coding Method for Multiplexed, Live Cell High Content Studies of Prostate Cancer
Fred Schaufele, Associate Professor, UCSF Diabetes Centre, United States of America

Mixing cell types in a well can improve a screen through either the multiplexing of different assays or the mimicking of cell-cell interactions found in a tissue. ‘Bar-coding’ methods that distinguish mixed cell populations will be described.

Coffee and Networking

Screening of Innovative HTS and HCS Assays in an Academic Environment
Kamyar Hadian, Group Leader, Helmholtz Zentrum München, Germany

Screening in the academic environment has highly emerged within the last few years. We have invested in the development of innovative biochemical, phenotypic and high-content assays (e.g. protein-protein-interactions, cell-based assay in stem cells or microtissues) for HTS or HCS.

Establishment of a Whole Animal HTS Novel Technology Platform for Anti-Bacterial Drug Discovery
Umayal Lakshmanan, Research Fellow/Project Leader, Experimental Therapeutics Centre, Singapore

Melioidosis is a serious emerging endemic infectious disease caused by Burkholderia pseudomallei (B.p), a gram-negative pathogen. Septicemic Melioidosis has a mortality rate of 50% even with treatment.  Like other gram-negative bacteria, B.p is resistant to a number of antibiotics and multi-drug resistant B.p is beginning to be encountered in hospitals. There is a clear medical need to develop new treatment options to manage this disease.  We set out to establish a biologically relevant assay to screen for antibacterial compounds and to use this platform to identify novel compounds that can modulate the Melioidosis infection. We used Burkholderia thailandensis (a BSL-2 class organism) to infect Caenorhabditis elegans and set up a surrogate infection model of Melioidosis that we could run in a 384 microtitre plate and establish a whole animal HTS assay. We have optimized and validated this assay in a fluorescence-based format that can be run on our automated screening platforms. This assay has now been used to screen over 300,000 compounds from our small molecule library and we are in the process of characterizing the hits obtained and select compounds for further studies. 

Strategic siRNA Screening Approaches to Targeting Cancer
Emma Shanks, Head of Screening, Beatson Institute for Cancer Research, United Kingdom

The RNAi Screening Facility at the Cancer Research UK Beatson Institute combines genome-wide siRNA screening with High Content Imaging and fluorescence-based phenotypic assays to target cancers derived from multiple tissue types. Permutations of synthetic lethality allow for novel target identification in i) defined genetic cancer backgrounds, ii) chemotherapeutic-resistant cancer lines and iii) in combination with pre-clinical or known drugs. Of central importance to our approach is the use of an appropriate and predictive model that facilitates translation of results towards the clinic, and our experiences with this will be discussed. 

Seeding Open Innovation in Drug Discovery and Translational Research through Collaboration Models Leveraging Government Funding: Mayo Clinic and Florida Translational Research Programs
Thomas Chung, Director of Outreach/Project Manager, Sanford Burnham Medical Research Institute, United States of America

With costs (>$1B per NCE) and duration (10-15Y) of traditional R&D as practiced, "big Pharma" has come under increased scrutiny and assault from disease advocacy groups, government and investment communities as being too high and long, stagnant, and unsustainable.  They have raised a clarion call for new innovative business models for drug discovery and development, in particular the participation the best of academia to catalyze new innovation and translational research.   Leveraging our Prebys Center's experience in  “open innovation” as a Comprehensive Screening Center of the NIH's Molecular Libraries Probe Production Centers Network (MLPCN), we established new models of academic drug discovery and development that  leverage alternative sources of government and public funding with clinical translational partners. In this talk, we provide a case study of the motivations and  working operational models and our strategic alliance and partnership with the Mayo Clinic and a more recent alliance with the State of Florida.

Pharmacophore-based Fragment Screening: An Efficient Approach for Lead Design
Thierry Langer, CEO, Prestwick Chemical, France

Professor Langer will showcase the results of a recent successful research project done at Prestwick Chemical: Using LigandScout's pharmacophore-based in silico fragment screening technology, and an intelligent fragment library, attractive starting points for a medicinal chemistry hit to lead optimisation program were discovered. Within 3 months from the start of the project, patentable hit compounds were obtained which then were expanded to lead candidates.

Lunch, Poster Viewing and Networking

Title to be Confirmed
Pavel Formitchov, Engineer, GE Healthcare, United States of America

Simplicity and Complexity – High Content Screening of Physiologically Relevant Models
Jacob Tesdorpf, Director, Perkin Elmer, Germany

Increasing efficiency of drug discovery is paramount and multiple approaches are supporting this objective. Better cellular model systems offer more relevant insight into the disease physiology while maintaining sufficient throughput to enable fast translation. Such models can also reveal early indicators of undesired effects and toxicity allowing leads to fail early and cheap. This talk will show how PerkinElmer technologies can help scientists to identify new compounds or toxic effects early in the drug discovery process by enabling work with complex cellular models such as primary human cells, iPS derived cells or 3D micro-tissues.

Session Moderated by
Rathnam Chaguturu, Founder and CEO/Senior Director, SRI International, United States of America

Panel Participants: Paul Diehl, Thierry Langer, Neil Emans, Susan Magdaleno, Pavel Fomitchov, Jacob Tesdorpf

Discussion Topics:

• Academic & Not-for-Profit Screening Operations


• Future of Pharma Discovery Platforms and Sites: Too Many Closures to Date?


• Novel & Enabling Screening Technologies in 2013


• Vendor/User Perspectives on HCA in 2013
  
  
• Outsourcing Chemistry Trends in 2013

Close of Day One and Drinks Reception

Using Silencer Select siRNA to Uncover Non-coding RNA (ncRNA) Function
Susan Magdaleno, Senior Manager, Life Technologies, United States of America

Transcriptome analysis has identified thousands of novel non-coding RNA (ncRNA) but their importance is largely unknown and untapped. We will present how Ambion RNAi technologies can be used to uncover ncRNA function in cell based assays.

Persomics Technology Allows on the Fly High Content Genomic and Diagnostic Screening
Neil Emans, CEO & Founder, Persomics, South Africa

Persomics technology allows on the fly genomic and diagnostic screening, through miniaturization of cell based experiments. In this presentation, we present how our technology can fundamentally speed screening at the interface of the human cell and genomic libraries. We can make it work on the fly.

Fusing RNAi Screening and Gene Expression Analyses to Reveal Pathway Responses
Alexander Bishop, Assistant Professor, University of Texas Health Science Center, United States of America

Previously it has been shown that RNAi screening and gene expression analyses do not provide any significant enrichment in their data on a gene level. Here we demonstrate that these platforms can be fused when combined on a pathway level.

Moving Beyond In-vitro Models: Addressing the Challenges of Pooled RNAi Screens in Xenografts
Paul Diehl, Director of Business Development, Cellecta, United States of America

To date, several groups have successfully run genome-wide in vitro RNAi screening using pooled libraries expressing a complex diversity of shRNA molecules. Integral to obtaining reliable and robust results with this technique has been the use of quantitative next generation sequencing to accurately assay hairpin representation levels in the endpoint populations of cells transduced with shRNA library. However, there are significant challenges in adapting the current pooled RNAi screening approaches to more sophisticated cell model systems, such as ex-vivo xenograft models. Our studies tracking the fates of thousands of individually barcoded implanted cells found that xenograft growth is characterized by a small subset of cancer cell sub-clones that ultimately produce the bulk of the resulting tumor mass. This phenomenon significantly impacts the ability to reliably detect shRNA-induced growth inhibition in these systems. To address this problem, we have developed a novel approach to constructing pooled shRNA libraries that enables effective viability screening in systems in which external parameters strongly influence cell growth rates, such as xenograft tumors. We will present preliminary data using this approach, as well as data from more conventional in vitro “drop-out” lethality screens, to identify genes essential for cell proliferation. The results demonstrate that complex pooled shRNA libraries offer an efficient and flexible tool for both in vitro and in vivo screens aimed at discovering potential cancer therapy targets.

Coffee and Networking

A Decade of RNAi Screening: Too Much Hay & Very Few Needles
Bhavneet Bhinder, Bioinformatics Engineer, Memorial Sloan Kettering Cancer Center, United States of America

RNAi screening will soon be celebrating 15 years of trials and tribulations; this occasion will be marked by an achievement of up to ~ 600 publications reporting on its use. Like many new technologies before it, it is plagued by controversy surrounding the growing evidence of disparate hit lists, dismal gene correlation at inter-screen level, and the lack of reproducibility. I will review the current landscape and will discuss simple ways to help remedy these concerns.

Pooled RNAi Screens to Identify Synthetic Lethals in ERBB2+ Breast Cancer Cells
Jose Silva, Assistant Professor of Pathology, Columbia University, United States of America

ERBB2 is a receptor tyrosine kinase amplified and overexpressed in 15-20% of breast tumors (ERBB2+ tumors) and is associated with a poor prognosis. Current therapies targeting ERBB2, have resulted in improvements in survival but innate and acquired resistance have increasingly occurred. By combining genome-wide RNAi loss-of-function screens with system biology interactome models we have recently found that the JAK/STAT3 pathway is activated in ERBB2+ breast tumors. Activation of STAT3 was found to be essential to maintain the homeostasis of these tumors as genetic and pharmacological inhibition of this pathway strongly compromised their viability.

Disease Biology Through Whole Genome RNAi Screening: The SOD1 and TDP-43 Connection
Balajee Somalinga, Instructor, University of Texas Southwestern Medical Center, United States of America

Proteinaceous inclusions in sporadic amyotrophic lateral sclerosis (ALS) contain TAR DNA binding protein (TDP-43), other ubiquitinated proteins but rarely contain superoxide dismutase 1 (SOD1). This has led to the hypothesis that SOD1-linked and sporadic ALS follow independent paths despite common pathophysiology. To understand the link between SOD1 and sporadic ALS a whole genome RNAi screen was carried out to identify modulators of SOD1 expression. Interestingly we identified TDP-43, a protein linked to sporadic ALS in the highest ranked protein network mapped from the hits. TDP-43 negatively regulates SOD1 and this could help explain the oxidative deregulation commonly observed in ALS.

Accepting and Meeting the Challenges of RNAi Screening
Scott Martin, Group Leader, RNAi Screening, NCATS, NIH, United States of America

RNAi screening has proved invaluable for illuminating gene function, but there is growing frustration with poor validation rates and a lack of correlation between similar screens. These issues and relevant strategies will be discussed.

The Reproducible RNAi Screen
Eugen Buehler, Group Leader, NIH Chemical Genomics Center, United States of America

We will describe our efforts to implement a screening pipeline that accounts for and leverages seed based  off-target effects, from library design all the way to follow-up experiments.

Lunch, Poster Viewing and Networking

Session Moderated by
Jim Inglese, Adjunct Investigator, National Institutes of Health, United States of America

Panel Participants: Rathnam Chaguturu, Deborah Collyar, Elizabeth Iorns, Douglas Storts

Discussion Topics:

• Data Reproducibility and its Impact on Much Needed Breakthroughs to Fight Disease


• How Good is Published Academic Chemical and RNAi Screening Data?


• Will Academia – Industry Collaborative Research Enhance Data Reproducibility?


• Is the “Anonymous” Peer Review Process to Blame?


• Authentication of Research Reagents 

• 1:00 - 1:30 Deborah Collyar
• 1:30 - 2:00 Elizabeth Irons
• 2:00 - 2:30 Douglas Storts

Workshop Concludes