Cancer Grand Challenges is a series of £20m ($25m) awards that give international teams of researchers the freedom to think differently, act creatively and explore truly innovative science to take on fundamental questions in cancer.
In recent years, scientists have been experimenting with ‘macromolecules’ to target and destroy cancer cells. A macromolecule is defined as any very large molecule, with a molecular weight exceeding about 1,500 Daltons. These macromolecules can disrupt the processes that cancer cells use to survive, for example by stopping them from growing or by flagging their presence to the body’s immune system. Importantly, they can be engineered to be far more specific and active than current small molecule therapies.
This approach is often effective on cancer cells in the laboratory, but unlike conventional ‘small molecule’ treatments, it is difficult to deliver these macromolecules systemically to the inside of cells where they need to act and engage with their target.
If we could develop approaches to deliver these macromolecules to any and every cell in the body, including the central nervous system, ensuring they crossed the cell membrane and engaged with their target, it would create new ways to treat cancer and could also have a significant impact on other diseases.
Barriers and opportunities
The exact barrier in delivering macromolecules is crossing the cell membrane to enter the cytoplasm and nucleoplasm where target molecules reside. Many molecules that bind to the cell surface enter endosomes but cannot escape that membrane compartment. Bacterial protein toxins have evolved mechanisms of endosomal escape and certain macromolecules, such as cyclosporin, have an intrinsic ability to cross membranes. Viruses can deliver both DNA and RNA into the cell, providing a precedent for an intractable problem.
New approaches to tackle this challenge could involve:
The use of novel nanoparticles that mimic viruses
Engineered proteins that use toxin like mechanisms
Exploiting a deep understanding of the design principles that allow certain macrocyclic peptides to cross the membrane by passive diffusion
It will also be important to measure target engagement as part of this challenge, so developing suitable assay systems and potent metabolically stable macromolecules will also be required.
Approaches should be practical, affordable and innovative around cellular mechanisms of uptake that can be developed for use in humans.
Vision and Impact
Success in answering this challenge would be the demonstration of efficient cellular entry and target engagement of a number of macromolecules in animal models. It would be desirable to demonstrate that the approach worked for multiple targets e.g. Myc, Ras, Mdm2, EWS-Fli1. Ultimately, a universal delivery system for macromolecules would be transformative allowing thousands of new targets to become “druggable “and improving outcome for cancer patients.
Addressing this challenge will require a multidisciplinary team, which may include expertise in material science, membrane chemistry, virology, microbiology, molecular cell biology and pharmacology.