Taking out cancer’s trash

Twenty years ago, precision medicines emerged that transformed cancer treatment. These medicines worked by blocking the activity of malfunctioning proteins that drive a patient’s specific form of the disease. But cancer is incredibly complex, and scientists working to apply this approach as broadly as possible faced challenges, including this: the majority of known cancer-driving proteins were considered “undruggable.”

What do we do about this? One way may be to help the cell take out its trash.

What does “undruggable” even mean?

The goal of cancer medicines is to stop abnormal cells from growing out of control. One strategy to achieve this is to target proteins that cause out-of-control growth and stop them from working. To do so, scientists design activity-blocking drugs that bind to highly specific locations on a target protein – like a key designed to fit only one specific keyhole.

However, many proteins – including a family called transcription factors, among the most commonly mutated proteins in cancer – don’t have the properties needed to create targeted drugs using classic medicinal chemistry approaches. In essence, these proteins are “undruggable” because they lack a keyhole. So, instead of dealing with keyholes, we’re trying to get rid of the whole protein, using an approach called targeted protein degradation.

Precision waste disposal

If you’ve studied basic biology, you might remember the analogy of a cell as a city with roads, power plants, warehouses, and more. Cells also have a waste disposal system, one specifically designed for proteins.

It involves a cellular machine called the proteasome, which is kind of like a compacting garbage truck that goes around the cell, breaking down old, unwanted or defective proteins. To identify which proteins to degrade, the proteasome looks for a chemical tag called ubiquitin (which is placed onto proteins by other specialized molecular machines).

If scientists can figure out how to tag a target protein with ubiquitin in just the right way, it could open the door for new potential therapies. With targeted protein degradation, we might be able to remove cancer-driving proteins from the cell entirely – including “undruggable” ones. This isn’t limited to proteins in cancer cells – targeted protein degradation could potentially help control “undruggable” proteins in other cells, such as in certain T cells to help improve outcomes of immunotherapy

Targeted protein degradation is still in its very early stages, and Novartis scientists are working hard to realize its potential for patients. Using tools like molecular glues, we’re trying to force the cell’s ubiquitin-tagging machinery to interact with target proteins, so that the proteasome can degrade them. We’re hoping that this approach has the potential to someday serve as a pillar for cancer care, and together with other promising technology platforms, give us new ways to overcome the complexity of cancer.