8:30 am

Coffee & Networking

8:55 am Chair’s Opening Remarks

Targeting the Previously Undruggable: Translational & Clinical Perspective of Targeting RAS

9:00 am Rigosertib is a Unique Small Molecule RAS Antagonist: Scientific & Clinical Studies

Synopsis

• Rigosertib targets RAS as a RAS mimetic interacting with its effector proteins

• Role of genetic and RAS Pathway Mutations in MDS

• An update of RAS in the clinic

9:30 am Vaccinating Against Mutant RAS – Results from TG01 Phase I/II Trial

Synopsis

• Results from 32-patient TG01 trial in resected pancreatic cancer

• Robust immune responses demonstrated against KRAS

• Overview of clinical and molecular outcomes

10:00 am RAS Mutation: Being Precise in Precision Medicine

  • Colin Lindsay Clinical Senior Lecturer, The University of Manchester; Medical Oncology Consultant , The Christie NHS Foundation Trust

Synopsis

• Clinical and translational perspective on previous clinical trial disappointments with RAS targeting

• Looking towards immunotherapy combinations with small molecules in the lung cancer landscape

• Examination of whole genome/exome sequencing results from RAS mutant lung cancer

10:30 am

Morning Refreshments & Networking

Enabling Structure Guided & Selective Targeting of RAS Proteins

11:00 am Disruption of the RAS-SOS1 Interaction – Enabling Lead Discovery by a Combination of High-Throughput & Fragment Screening

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

11:30 am Discovery of BI-3406: A Potent & Selective SOS1::KRAS Inhibitor Opens a New Approach for Treating KRAS-Driven Tumours

  • Michael Gmachl Principal Scientist, Regional Center Austria , Boehringer Ingelheim

Synopsis

• BI 3406 selectively binds to SOS1 and blocks the interaction with KRAS, irrespective of the KRAS mutation

• BI 3406 causes RAS GTP and pERK reduction and inhibits cell growth of KRAS mutated cell lines, carrying most of the typical KRAS mutations (i.e. G12D, G12V, G13D and others)

• BI 3406, when administered orally to tumour bearing mice, causes a dose dependent tumour static effect that can be converted into regressions when combined with MEK1 inhibition

12:00 pm Drug Development Against KRAS Surrogate Targets

  • Daniel Abankwa Professor of Cellular Tumour Biology , University of Luxembourg

Synopsis

• Selective targeting of KRAS, but not H-RAS may specifically eliminate cancer stem cells (CSC)

• To this end, we developed novel inhibitors against PDE6D/ PDEdelta, a surrogate target of KRAS, which realise KRAS selectivity and thus anti-CSC activity

• Secondly, we describe a new mechanism of how Hsp90 inhibition likewise selectively targets KRAS; novel small-molecule Hsp90/Cdc37 protein-protein interface inhibitors are presented

12:30 pm The Role of the Activator of the Small GTPase RAC, TIAM1, in Mutant KRAS Driven Lung Adenocarcinomas

  • Angeliki Malliri Senior Group Leader & Professor of Cell Biology, Cancer Research UK Manchester Institute , The University of Manchester

Synopsis

• The small GTPase RAC has been shown to be required for KRAS-induced lung tumourigenesis

• TIAM1, one of the RAC activators, is a RAS effector protein

• The role of TIAM1 in the formation and progression of mutant KRAS-driven lung adenocarcinoma and its mechanism of action will be discussed

1:00 pm

Networking Lunch

Advancing Discovery & Characterisation of Novel Anti-RAS Strategies

2:00 pm Targeting RAS-Driven Tumour by Exploiting Vulnerabilities in the RAS Network

  • Sara Mainardi Senior Postdoctoral Researcher , Netherlands Cancer Institute

Synopsis

• Mutant RAS is still dependent from upstream stimulation

• Inhibition of upstream RAS stimulation (SHP2) confers sensitivity to downstream (MEK and ERK) inhibitors

• Triple vertical targeting of the MAPK pathway enhances anti-Tumour efficacy and prevents resistance

2:30 pm RAS Conformational Dynamics & Its Influence on RAS Drug Discovery

  • Tatu Pantsar Marie Skłodowska, Curie Fellow , University of Tübingen

Synopsis

• Why is it important to understand RAS dynamics?

• What do we really understand of RAS dynamics?

• How does RAS dynamics impact on drugging RAS?

3:00 pm Targeting Mutant KRAS Tumours with a Functionalised Anti-KRAS Macromolecule

  • Nicolas Bery Postdoctoral Research Scientist , University of Oxford

Synopsis

• Development of biosensors to characterise anti-RAS small-molecules and macromolecules (i.e. intracellular single domains)

• Discovery and characterisation of novel KRAS-specific macromolecules

• The specific inhibition of mutant KRAS tumours by functionalised macromolecules

3:30 pm Chair’s Closing Remarks & Close of RAS- Targeted Drug Discovery Summit Europe

  • Daniel Abankwa Professor of Cellular Tumour Biology , University of Luxembourg