January 29 – 31 2019

Boston, MA

 

 

Day One
Wednesday January 31st, 2018

Day Two
Thursday February 1st, 2018

08.00
Coffee & Registration

08.50
Chairman’s Opening Remarks

  • Jeffrey H. Hanke Executive Vice President, Research and Development, and Chief Scientific Officer, TESARO

Laying the Foundations for DNA Damage Response Therapeutics: Advancing Synthetic Lethal Screening

09.00
Leveraging Genome-wide CRISPR Screens and Synthetic Lethal Interactions for Novel Cancer Therapeutics

  • Stephane Angers Professor, Faculty of Pharmacy & Dept of Biochemistry, University of Toronto

Synopsis

• Novel genome-wide CRISPR-Cas9 functional screening approaches to probe the genetic wiring of cancer cells
• Identification of “core” fitness genes required for the growth of all cell types and of“context-specific” fitness genes required specifically for a limited number of cancer types
• Case study in pancreatic cancers revealing the Wnt receptor FZD5 as one such “context-specific” fitness gene for which we have developed a monoclonal antibody exhibiting tumor growth inhibition
• Performing CRISPR-Cas9 essentiality and chemogenomic screens to reveal new genetic vulnerabilities of Glioblastoma stem cells and identify mechanisms of drug resistance and hypersensitivity

09.30
Identifying Differential Dependencies on Epigenetic Pathways and Synthetic Lethal Relationships with CRISPR Pooled Screening of Hundreds of Cancer Cell Lines

Synopsis

• Identifying both pan-essential genes as well as genes which display selective sensitivity upon knockout with high quality and reproducible data from CRISPR pooled screening
• Integrating pooled screening data with other genomic information can aid in the identification of novel synthetic lethality interactions
• Gene amplifications can generate false positive data in CRISPR pooled screening
• Determining the domain responsible for the observed proliferation effect with domain-focused CRISPR screening

10.00
Panel: Comparison of Approaches and Best Practices for Synthetic Lethal Screening

  • Kevin Coleman Executive Director, Translational Research & Development, Experimental Biology, TESARO
  • Stephane Angers Professor, Faculty of Pharmacy & Dept of Biochemistry, University of Toronto
  • Alexandra Grassian Senior Scientist, Epizyme

Synopsis

• Assessing the benefits and drawbacks of CRISPR full knockout, CRISPR-I/CRISPR-A and RNAi
• Examining overlap among different silencing modalities
• Optimal practices for double-knockout library screening to identify synergistic effects and reliably recognize artefacts
• Capitalizing on screening data – planning chemical pipelines to identify inhibitor compounds for targets nominated by screening efforts

10.45
Speed Networking & Refreshments

11.45
Patient Organoids as a Platform for Drug Discovery: Development of Novel Synthetic Lethality Targets

Synopsis

• Next generation targeted drugs based on synthetic lethal targets toward MYC, TP53 and KRAS
• Functional testing of individual patient’s organoids with single and combinatorial agents
• Pharmaceutical partnership to guide successful drug development

Optimizing Bioinformatics & Holistic Approaches

12.15
Exploiting Synthetic Lethality and Induced Essentiality in the Context of Cancer Metabolism with a Combined Computational and Metabolomic Approach

Synopsis

• Overview of the landscape in cancer metabolism and Metabomed’s approach to identifying synthetic lethal and induced essential targets in different cancer types
• Identifying and targeting synthetic lethal vulnerabilities in the context of cancers characterized by impaired or lost function of the SDH complex
• Exploiting specific metabolic stressors of the tumor microenvironment to reveal induced essential targets
• Passenger deletions alter tumor metabolism, revealing synthetic lethal vulnerability
• Computational identification of Synthetic Lethality networks as a tool to generate a stratification strategy for drug therapies based on synthetic lethality

12.45
Prioritizing Targets for Therapeutic Development by Defining a Cancer Dependency Map

  • Aviad Tsherniak Associate Director, Cancer Data Science, Broad Institute of MIT and Harvard

Synopsis

• Understanding the relationships between the genetic alterations of cancer and cancer dependencies by building a “cancer dependency map”
• Systematically identifying genetic and small molecule vulnerabilities and determining the molecular markers that are associated with them
• Developing computational methods that correct off-target effects in RNAi screens (DEMETER) and copy number effects in CRISPR screens (CERES)
• Our analysis reveals hundreds of genes that are preferential dependencies in subsets of cell lines

13.15
Harnessing Synthetic Lethality to Predict Patient Response and Synergistic Combinations in Cancer

  • Eytan Ruppin Professor of Computer Science, Director of the Center of Bioinformatics and, Computational Biology (CBCB), University of Maryland

Synopsis

• Exploring ISLE (Identification of clinically relevant Synthetic Lethality), a data-driven approach that mines the TCGA cohort to identify a subset of clinically relevant SL interactions (cSLi) from an initial pool of screened SL interactions
• Testing a select set of predicted cSLi via new experiments, validating their predicted context sensitivity and demonstrating their utility in predicting synergistic drug combinations
• Evidence of successful prediction of patients’ treatment response and predicted cSLi providing readily available biological signatures for patient treatment stratification
• Taken together, ISLE complements existing mutation-based methods for precision cancer therapy, extending their scope from few hundreds of cancer driver genes to that of the whole genome

13.45
Lunch & Networking

Overcoming the Lack of Single Agent Activity: Finding Effective Combinations

14.45
PARP Inhibition Meets Tumor Immune Modulation: Rationale and Patient Positioning Considerations

  • Jeffrey H. Hanke Executive Vice President, Research and Development, and Chief Scientific Officer, TESARO

Synopsis

• Rationale and opportunity for combination of PARP inhibitors with immune checkpoint modulation
• Leveraging the rapidly emerging key clinical data on PARP inhibitors such as niraparib
• Examining approval pf PD1/L1 immune checkpoint inhibitors across tumor types

15.15
Synthetic Lethality as a Tool to Resuscitate Abandoned Drugs That Experienced Poor Single Agent Activity

  • René Bernards Professor of molecular carcinogenesis, Netherlands Cancer Institute

Synopsis

• Exploring relevant synthetic lethality screening strategies
• Identifying effective drug combinations
• Harnessing synthetic lethality to find drug response biomarkers
• Analyzing effective validation strategies

15.45
Panel: Mapping the Landscape of Future Combinations for Synthetic Lethal Drugs

  • Jeffrey H. Hanke Executive Vice President, Research and Development, and Chief Scientific Officer, TESARO
  • René Bernards Professor of molecular carcinogenesis, Netherlands Cancer Institute
  • Eytan Ruppin Professor of Computer Science, Director of the Center of Bioinformatics and, Computational Biology (CBCB), University of Maryland

Synopsis

• Examining the industry’s current combination trends and identifying the avenues that will be of the highest therapeutic value in the next five years
• Preparing for the implementation of these with the wave of new synthetic lethal drugs set to enter the clinic
• Exploring chemical interactions between targeted therapies and immunotherapies
• Using these insights to balance synthetic lethal drugs with an immunotherapy that can take advantage of the local conditions
• Methods for overcoming potential phasing issues

16.30
Afternoon Refreshments & Networking

17.00
Synthetic Lethality Roundtables

Synopsis

Mechanisms of Resistance

• Explore methods for overcoming target-mediated and non-targetmediated resistance
• What methods best determine origins of resistance?
• How can we leverage these to re-sensitize tumors to a synthetic lethal drug?

Expanding Synthetic Lethality based Therapies Beyond Oncology

• How can we widen the scope of synthetic lethal drugs to treat a more diverse range of diseases?
• How do we navigate the landscape of possible conditions in which synthetic lethal interactions play a key role and can be targeted?

Required Steps for Developing Context Independent Synthetic Lethal Drugs

• How can screening methods best be used to identify synthetic lethal interactions with the potential to be highly stable across contexts?
• What types and combinations of models are required to comprehensively test therapies across contexts?

18.00
Chairman’s Closing Remarks

  • Jeffrey H. Hanke Executive Vice President, Research and Development, and Chief Scientific Officer, TESARO