Pancreatic cancer remains one of the most difficult cancers to treat. In the United States alone, the disease claims more than 50,000 lives each year, a reality that physician-scientist Steven Corsello, MD, sees up close in his work as an oncologist.
“Pancreatic cancer is a deadly disease, and as an oncologist I see every day how limited our current treatments still are,” Corsello explains.
Corsello’s research, which focuses on discovery of cancer vulnerabilities, aims to close this gap with a new and unusual strategy for fighting cancer. Instead of trying to block the proteins that help tumors grow, his lab is working on drugs designed to make cancer cells destroy those proteins themselves. These experimental drugs, known as molecular glues, take advantage of the cell’s own cleanup system, redirecting it to eliminate parts the cancer depends on to survive.
The idea is still in early stages, but it has drawn major interest. Corsello and his collaborator, chemical biologist Nathanael Gray, PhD, recently received The Mark Foundation Drug Discovery Award, a competitive grant that supports high-risk, high-reward cancer research and helps move promising discoveries closer to clinical trials. The award provides funding and industry-level guidance to help laboratory research develop into real therapies.
We spoke with Dr. Corsello about how molecular glue drugs work, why pancreatic cancer has been so hard to treat, and what it will take for this new approach to reach patients.
The Conversation
Molecular glue degraders are gaining attention as a new type of cancer therapy. For readers unfamiliar with the concept, what exactly does a “molecular glue” drug do, and how does that approach differ from traditional drugs?
Most traditional drugs work by blocking the activity of a protein that helps a cancer cell grow. Molecular glue drugs take a different approach. Instead of blocking a protein, they help bring two proteins together that normally would not interact.
When this interaction happens, one of those proteins is recognized by the cell’s natural disposal system and gets broken down. In other words, the drug causes the cancer cell to destroy one of its own critical parts, rather than just slowing it down.
The molecular glue degrader strategy allows us to target proteins that were previously very hard to drug using conventional methods.
These drugs have already shown success in certain blood cancers. What has made it harder to apply the same strategy to solid tumors like pancreatic cancer?
Some of the first molecular glue drugs, such as thalidomide-related medicines, work very well in certain blood cancers because they target proteins that those cancers depend on but that other cells do not.
Pancreatic cancer is different. The proteins that keep pancreatic cancer cells alive are not the same ones targeted by existing molecular glue drugs. That means we need to find new targets that are essential for solid tumors, and then design drugs that can specifically eliminate those targets.
Your work focuses on a protein called TRIM21, part of the cell’s cleanup machinery. What makes TRIM21 a good candidate for this strategy, and how often is it present in pancreatic cancer?
TRIM21 is part of a group of proteins that help mark other proteins for destruction. You can think of it as part of the cell’s recycling or cleanup system.
What makes TRIM21 interesting is that it seems particularly good at breaking down large protein structures inside cells, and we found that pancreatic cancer cells often have high levels of it.
By testing many different compounds in cancer cell models, we discovered a drug that unexpectedly binds to TRIM21 and causes TRIM21 to destroy a structure that cancer cells need to survive. Working with medicinal chemists at Stanford, we then modified that compound to make it stronger and more selective, with greater potential for eventual clinical use.
A major challenge in cancer drug development is killing cancer cells without harming healthy ones. How do you make sure a molecular glue has a stronger effect on tumor cells than on normal cells?
That is one of the most important questions we have to answer before a drug can move forward.
Our initial findings show that the TRIM21 molecular glues immediately kill cancer cells via a process called programmed cell death, which makes us really hopeful! The impact of TRIM21 molecular glues on normal, healthy cells was smaller and more variable. We are conducting additional experiments to study this difference.
You recently received The Mark Foundation Drug Discovery Award with your colleague Dr. Nathanael Gray. How will this award help move this work toward clinical trials?
This award aims to bridge the gap between early laboratory discoveries and the point where a drug is ready to be tested in patients.
The funding will allow us to improve the chemistry of our molecular glue compounds, study how they behave in animals, and do the kinds of safety and pharmacology experiments that are required before a therapy can enter clinical trials.
What milestones would tell you this approach is working, and what has to happen before it could be tested in patients?
One key step is showing that the drug works in models that closely resemble human tumors, including pancreatic cancer cells grown directly from patient samples.
Before any human trial, we also need to complete a large number of safety studies and drug-development steps required for an Investigational New Drug application. That includes making sure the drug can be produced reliably and in large enough quantities, and securing the funding needed to run clinical trials.
Pancreatic cancer has historically been very difficult to treat. If this TRIM21 molecular glue strategy works, how could it change the treatment landscape?
I see firsthand how our current treatments for advanced pancreatic cancer remain largely limited to chemotherapy drugs with insufficient efficacy. The treatment landscape may be starting to improve with the ongoing development of a class of drugs called KRAS inhibitors, which target a gene responsible for uncontrolled tumor cell growth. By developing drugs against unique new therapeutic targets such as TRIM21, we hope to develop more effective drug combinations and improve treatment outcomes.
This work is made possible by the support from The Mark Foundation for Cancer Research as well as from the Damon Runyon Cancer Research Foundation, Stanford Cancer Institute, and Stanford’s Innovative Medicines Accelerator.
