New drug reduces tumor volume in mouse model for aggressive lung cancer

Deltafluorine shows initial success in treating difficult-to-treat form of cancer

To the point

• New approach: Instead of directly blocking the hard-to-attack KRAS cancer protein, deltafluorine switches off a helper protein that supports KRAS.
• Development in the laboratory: The durg was designed to bind particularly strongly and permanently to its target.
• Initial success in animal experiments: In an aggressive lung cancer mouse model, tumor growth was significantly slowed and important growth signals were inhibited.

KRAS is a protein in our cells that controls when a cell should grow or divide. Mutations in the KRAS gene are one of the most common triggers for cancer. For a long time, KRAS was considered virtually untreatable with drugs. Active substances are now available for a few variants, but targeted therapies are lacking for most.

A research team at the Max Planck Institute for Molecular Physiology in Dortmund has therefore developed a new approach: instead of inhibiting KRAS itself, they attack PDEδ. This helper protein transports KRAS to the right location in the cell membrane so that it can transmit its growth signals. If PDEδ is switched off, KRAS loses a crucial part of its function.

Development of deltafluorine

To effectively block PDEδ, the researchers designed deltafluorine. This fits into PDEδ like a matching key and binds to it permanently. This reliably deactivates the helper protein. In addition, deltafluorine is particularly stable and is not easily broken down in the cell, which can enhance its effect.

Successful test in mouse model

Together with researchers at the Max Planck Institute for Biology of Ageing, deltafluorine was tested in a particularly aggressive mouse model for lung cancer. This cancer originates from a mutation in the KRAS gene and hardly responds to conventional chemotherapy. After only 21 days of treatment, CT analyses showed that the tumor volume was significantly lower than in untreated animals. The joint project of the two Max Planck Institutes has now been published in the Journal of Medicinal Chemistry.

The results are important initial evidence that blocking PDEδ with deltafluorine can also slow the growth of KRAS-driven tumors in living organisms. "We were surprised to observe such a clear effect with the new drug in this aggressive model. The research is still in its early stages, but the result is a good first step," says Maxim Hützen, one of the study's lead authors. "This was made possible by our close collaboration with the Comparative Biology service unit, which supported us with the treatments, and Phenotyping, with which we established the method for high-resolution 3D measurement of tumors in the mouse lung." 

"In the long term, this approach could be a new opportunity for aggressive cancers for which there are only limited effective targeted therapies," said Ron Jachimowicz, who led the study.