Molecular Level Pilot: Improving Outcomes for RAS-related Cancers

The molecular level pilot of the Joint Design of Advanced Computing Solutions for Cancer (JDACS4C) program builds on the accomplishments of the ongoing NCI RAS Initiative.

The team is deepening understanding of RAS protein biology and discovering insights into possible new treatment options for RAS-related cancers by integrating next-generation experimental data with large-scale computational simulations.

In the long term, these improved analytical capabilities, coupled with advanced computational simulations, will enable additional discoveries of important cancer protein interactions, beyond RAS, and cell membrane-initiated signaling cascades at unprecedented scale and fidelity. This will lead to greater biological understanding of the disease, and new insights that will accelerate the development of drugs to target RAS and other cancers associated with undruggable targets.

The goal of the pilot is to deepen understanding of RAS biology and identify new drugs for RAS-related cancers through the integrated development and use of new simulations, predictive models and next-generation experimental data.

Pilot Leads

With shared expertise across the JDACS4C collaboration, this pilot is jointly led by:

  • Dr. Dwight Nissley, Frederick National Laboratory for Cancer Research
  • Dr. Frederick Streitz, Lawrence Livermore National Laboratory

Aims of the Pilot

  • Develop multiscale modeling capabilities to investigate RAS dynamics on cell membranes
  • Understand how RAS and extended RAS complexes are activated and simulate RAS-RAF interactions on realistic, lipid-bilayer membranes
  • Develop machine learning-enabled dynamic model validation approach to high-fidelity simulation

Current Progress

The multi-disciplinary pilot team has leveraged computational approaches to address experimental gaps and develop multi-scale modeling and machine learning capabilities, including:

  • Experimentally measured key protein-protein (RAS-RAF) and RAS-lipid interactions using Cryo-EM and X-ray/neutron scattering
  • Integrated these observations into predictive, multi-scale molecular dynamics simulations for membrane lipids, RAS-membrane interactions, and RAS activation

Together, the new approaches support the biophysical and computational elements needed to develop new insights for RAS activation and RAS intracellular signaling, leading to potential new therapies targeting RAS.

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