The Good Fight: Resisting Resistance

“For a lot of people, the revolution isn’t here,” says Dr. Caroline Robert, Head, Dermatology Unit at the Institut Gustave Roussy, the largest cancer center in France and Co-Chair of the MRA Grant Review Committee.

“We know that some people will do less well than others,” says Robert, “but honestly, when we begin treatment, we can’t predict who will respond, so we need new biomarkers.” Dr. Robert’s work focuses on resistance, where treatment either stops working—a term called “acquired resistance” or where patients do not respond to any therapy at all—a term called “primary resistance.”

Dr. Robert is a recipient of a 2018 Team Science Award and is spearheading a three-year project funded by MRA seeking to learn why some cancer cells, instead of dying, adapt and modify their protein and messenger RNA production in response to treatment. Knowing this will help clinicians better identify when to provide treatment, when to stop, and better predict how a patient is likely to respond to treatment prior to starting it.

Hearing Dr. Robert talk about her work sounds akin to a general preparing for battle: “I want to kill melanoma cells. I don’t care what tool I use to do it,” she says. Robert tries to think like the enemy. “We need to put ourselves in the role of the cells: What would we do if we were trying to invade someone? We would hide, eat whatever is available—these cells eat what other cells don’t want—and we would wait. We know they hide because they appear years later and we’re trying to figure out where they’re hiding so we can stop their reappearance.”

Dr. Caroline Robert presenting at the 2019 MRA Scientific Retreat

MRA-funded research is particularly important in advancing this knowledge. Despite targeted therapies killing the majority of tumor cells, often a small population of drug-resistant “persister” cells remain by making large-scale changes to their protein expression patterns. “Cells are getting smarter and are modifying themselves so we need to focus on the nexus,” says Robert, referring to a complex of proteins. Blocking a component of the protein complex that translates the genetic code has the potential to inhibit these evasion tactics.

For patients whose tumors are regressing, Dr. Robert and her team take samples and study the expression of the genes. They are looking closely at the tumor cells that persist in the face of targeted therapy, and are testing a new protein inhibitor designed to kill these cells. Lab results with mouse models are promising and suggest that when combined sequentially with already existing targeted therapies, this new inhibitor enhances tumor cell death.

In time, Dr. Robert hopes to begin testing this work in the clinic with patients. If successful, it could represent a new chapter in the melanoma playbook—one that prolongs the length of time that treatment is effective and addresses resistance head on.