Pre-Conference Workshop Day

8:30 am Registration Opens

Workshop A

9:00 am Design Principles of Covalent Fragment Libraries

  • Michael Shaghafi Associate Director, Frontier Medicines
  • Adam Rabalski Senior Scientist II Chemical Biology & Proteomics , Scorpion Therapeutics

Synopsis

Targeted covalent inhibition has renewed the landscape for the undruggable genome and previously hard to drug targets. There are significant advantages of covalent fragment based drug discovery, and this now represents a promising methodology to discover and validate novel targets. This session will consider the design principles behind the development of a covalent fragment library, utilising literature and experiences harnessing such therapeutics, and delve into the utility of such approaches to navigate the landscape of RAS pathway targeted therapeutics.

In this workshop, we will:

  • Review present recent considerations in the design of covalent fragment libraries
  •  Consider methodologies of covalent fragments for targeted therapeutics against RAS mutant cancers
  • Discuss the advantages and future potentials behind utilising covalent fragment libraries to discover and validate RAS pathway targets

Workshop B

9:00 am Patient Selection & Stratification in RAS Targeted Therapeutics Clinical Trials

Synopsis

Patient characteristics and stratification factors are critical features which can influence
the outcome of clinical trials. This is a key consideration which must be taken into account when we design, develop and conduct clinical trials for anti-RAS therapeutics. However, understanding the patient characteristics, truly capturing how to implement this into clinical trials and what this may alter for the outcome of the trial is an important factor for debate, and one which may alter the trajectory of successful RAS therapies reaching the patient.

This workshop will consider:

  • The essential patient characteristics and stratification factors which should be considered
  • The existing literature for RAS therapeutic trial design with critical patient mapping implemented
  • The future of RAS mutant cancer therapeutics, should this be implemented rapidly and effectively

11:00 am Morning Break

Workshop C

12:00 pm Targeted Delivery of Anti-RAS Therapeutics

Synopsis

With the success of Sotorasib, RAS has now finally been successfully drugged with a covalent inhibitor. Now, the landscape of novel modalities being utilised to target the RAS pathway is continuing to progress and demonstrated fantastic progress, such as promising updates from RAS degraders, monobody approaches and KRAS vaccines. Despite this huge promise, the critical question of effective and targeted delivery of such therapeutics remains a key bottleneck for this community. This workshop will consider the successful targeted delivery of therapeutics targeting RAS-mutant cancers.

In this session, we will consider:

  • Challenges presented with effective delivery of RAS therapeutics
  • Reviewing the varying modalities and associated difficulties targeting RAS
  • Rethinking approaches to improve targeted delivery of effective RAS targeted therapies

Workshop D

12:00 pm Benchmarking Animal Models & Systems Being Used to Compare Therapeutic Efficacy & Translation

Synopsis

Heterogeneity with KRAS-mutant tumours may explain the poor efficacy of nonspecifically targeting KRAS drugs. As this community continues to develop selective
inhibitors targeting specific KRAS mutations, it is critical that we utilise effective models
and systems to guide the development of KRAS specific therapies with high efficacy, and
optimised translation into the patient. This workshop will benchmark pre-clinical models being utilized across the community and consider emerging novel.

  • Reviewing literature surrounding optimised use of pre-clinical animal models with RAStargeted therapeutics
  • Discussing how we can best utilise models and systems to understand and enhance
    therapeutic efficacy and translation

2:00 pm Afternoon Networking Break

Workshop E

3:00 pm Intrinsic & Adaptive Resistance

Synopsis

Tumors consist of heterogenous populations of cells that are subject to continued mutational processes. Under the selection of front-line targeted therapies, specific mutations permit therapy escape of individual cells that re-seed tumors. A deeper understanding of the kinetics of tumor evolution at the single cell level can inform specific combination opportunities to thwart these processes. Vertical pathway combinations, implementation of new therapeutic modalities and combination with I/O agents are opportunities to overcome resistance to frontline RAS targeted therapies and improve overall PFS.

  • Review of clinical and pre-clinical data for on-target and network adaptive resistance mechanisms to KRASG12C inhibition.
  • Therapeutic approaches to overcome acquired and adaptive resistance to RAS targeted therapeutics.
  • Discuss the future opportunity of identifying and targeting drivers of Tumor Evolution to provide upfront combination therapies that may yield more durable patient responses by thwarting the acquisition of resistance at inception

Workshop F

3:00 pm The RASopathies – The Evolving Field & Mechanistic Understanding

  • Nancy Ratner Co-Leader, Rasopathy Program, Professor of Pediatrics, Cincinnati Childrens Hospital Medical Center
  • Pau Castel Assistant Professor, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Perlmutter Cancer Center

Synopsis

The RASopathies are a group of rare genetic conditions caused by mutations in
genes of the RAS-MAPK pathway. Abnormalities of this pathway have effects on
development and can cause several different syndromes. With emerging literature
expanding the understanding of this pathway, the therapeutic application of this
critical signalling pathway is becoming more evident and it is not surprising that
the RAS-mutant cancer community has entered into an era of drug repurposing
and cross-learnings, that are ever important for both RASopathy and RAS-mutant
cancer patients.

In this workshop we will:

  • Describe the different RASopathy syndromes and interplay with RAS-mutant cancers
  • Discuss the molecular mechanisms of pathogenesis of RASopathies and the animal models for these disorders
  • Existing and future potential for drug repurposing within the RAS-MAPK pathway

5:00 pm End of Pre-Conference Workshop Day