8:20 am Chair’s Opening Remarks

8:30 am Targeting KRAS Directly with Novel Drug Discovery Efforts at the NCI RAS Initiative

  • Dominic Esposito Director, Protein Expression Laboratory, NCI RAS Initiative, Frederick National Laboratory for Cancer Research

Synopsis

• The NCI RAS Initiative is developing new approaches for direct targeting of KRAS
• New technologies and assays from the RAS Initiative can enable other drug discovery efforts on RAS
• Collaborative efforts between industry, academic, and the RAS Initiative have had significant impacts on improving our understanding of the biochemistry and biophysics of RAS at the plasma membrane

Rising to the Undruggable Challenge: Delivering a New Pass Forward to Target RAS with Novel Strategies

9:00 am Mutation-Specific Strategies for Targeting RAS Driven Diseases

Synopsis

  • RAS mutations cause changes in protein dynamics that lead to dramatic changes in protein behavior
  •  Changes in protein behavior lead to changes in regulatory mechanisms and signaling
  • These changes may present as mutation-specific vulnerabilities for therapy

9:30 am Allosteric Modulation of KRAS by G12X Mutations

  • Antti Poso Professor of Drug Design, University of Eastern Finland & University of Tübingen

Synopsis

  • KRAS long timescale dynamics investigated by extensive atomistic molecular dynamics simulations reveals complex allosteric signaling network within the protein
  • Dynamics of KRAS is altered by G12X missense mutants via the hydrophobic allosteric network. This is mutation-specific and the effect on KRAS dynamics is especially manifested in the effector protein binding interface
  • Different KRAS G12X mutations are not equal; therefore, this should be carefully considered in KRAS targeting and therapies

10:00 am Real-World Data: Importance of Monitoring KRAS Mutations in Blood

Synopsis

  • Why is it important to monitor KRAS in blood with ddPCR?
  • Analytical, clinical and real-world data for KRAS G12C mutations in NSCLC
  • Bringing blood-based diagnostics from initial discovery to the clinic

10:15 am Speed Networking & Morning Refreshments

  • Dmitri A. Petrov Michelle and Kevin Douglas Professor of Biology Stanford University, D2G Oncology Scientific Founder

11:45 am RAS Protein Flexibility or How to Target Cryptic Pockets to Drug the Undruggable Master Oncogene

  • Laurent Debussche Vice President, Global Head Molecular Oncology Research Therapeutic Area, Sanofi R&D

Synopsis

  • RAS is a very flexible protein without any apparent druggable pocket which has resisted three decades of efforts to drug it
  • Cryptic or induced pockets can be identified in addition to so-called SII pocket
  • DNA-encoded library approach is a powerful approach to drug cryptic pockets such as SII pocket

12:00 pm Rigosertib: Targeting the Ras+ Pathway and Clinical Trials in MDS and Beyond

Synopsis

  • Rigosertib is a Ras mimetic; but how does it target constitutively activated pathways in cancer?
  • What is the role of Ras+ in myelodysplastic syndromes with an introduction of clinical trials underway; focusing on pivotal Ph 3 Trials in myelodysplastic syndromes.
  • The Rasopathies are a group of genomic Ras+ driven disorders in childhood, requiring innovative approaches targeting the abnormal pathways.

12:15 pm Disruption of the RAS-SOS1 Interaction – Enabling Lead Discovery by a Combination of High-Throughput and Fragment Screening

  • Benjamin Bader Senior Scientist, Small Molecule Innovation, Bayer AG

Synopsis

  • Combination of high-throughput & fragment screening enabled a new approach to target KRAS
  • Structure-guided optimization of potent and selective SOS1 inhibitors
  • Cellular data support a possible combination potential of SOS1 inhibitors with covalent inhibitors of KRASG12C

12:45 pm Membrane Binding and Druggability of RAS

  • Alemayehu Gorfe Associate Professor McGovern Medical School, University of Texas Health Science Canter at Houston

Synopsis

  • The genesis of RAS allostery, and its impact on current efforts toward direct RAS inhibitors
  • Dynamics-guided computational and experimental approaches for lead generation
  • The relevance of RAS membrane binding, orientational dynamics, and self-assembly for the development of potentially selective inhibitors

Translating Effective Anti-RAS Strategies into Novel Cancer Therapies

1:15 pm Networking Lunch & Poster Session

2:15 pm Targeting Upstream Activation of Mutant KRAS via Allosteric Inhibition of SHP2 Phosphatase

  • Huaixiang Hao Investigator III, Novartis Institutes for BioMedical Research

Synopsis

  •  The newly appreciated role of RTK and SHP2 for mutant KRAS activation
  • The RTK/SHP2 mediated MAPK pathway feedback activation upon ERK inhibition
  • Potential mechanisms of resistance to SHP2 inhibitors

2:45 pm RAS Inhibitory Biologics – A Novel Approach to Cancer Therapy

  • Ralph Minter Senior Director, Fellow, Antibody Discovery and Protein Engineering (ADPE), AstraZeneca

Synopsis

  • Overcoming engineering challenge of identifying selective and potent antibody-like proteins to target RAS
  • Mechanism of action and pros and cons against small molecule approaches to target RAS
  • Optimization of biologics delivery to enable viable clinical strategies

 

3:15 pm Vaccination Against Mutant RAS in Resected Pancreatic Cancer

Synopsis

  • Review of Targovax’s TG peptide vaccine program, which targets all codon 12 and 13 RAS mutations in parallel
  • Results from the recently completed 32-patient TG01 mutRAS vaccination trial in resected pancreatic cancer to be presented
  • Data shows robust levels of mutant RAS immune activation and a signal of clinical efficacy

 

3:45 pm Afternoon Refreshments & Poster Session

4:15 pm Intracellular Antibody Fragments as Starting Points for Drug Discovery and as Macrodrugs for Therapy

  • Terry Rabbitts Professor of Molecular Immunology, Weatherall Institute of Molecular Medicine, University of Oxford

Synopsis

  • Discovery of novel RAS-binding compounds using intracellular antibody competition in compound library screens for inhibitors on protein-protein interactions
  • Using intracellular antibodies screening methods to develop RAS isoform specific macromolecular drugs (macrodrugs)
  • Employing intracellular antibody macrodrugs to invoke KRAS-specific proteosome degradation in KRAS-mutant cells

4:45 pm Discovery of Novel RAS Vulnerability using Monobodies

  • Shohei Koide Professor of Biologics Design , New York University School of Medicine and Perlmutter Cancer Center

Synopsis

  • The current challenge in developing RAS-targeting drugs suggests the need for innovative approaches for discovering methods to control RAS function
  • We have established a platform to rapidly develop monobodies, synthetic binding proteins, with high selectivity and potency and to utilize them as genetically encoded “tool” biologics against intracellular targets such as RAS
  • Our approach has led to the discovery of novel sites for allosterically inhibiting RAS, which guides drug discovery and gives new insights into the molecular mechanism underlying RAS signaling

5:15 pm Chair’s Closing Remarks & End of Day One

7:00 pm Registration & Networking Coffee