Wnt Pathway Emerges as Attractive Target in CRC

Lukas E. Dow, PhD

Wnt could be a prime target and immune agonist in colorectal cancer (CRC), given that the protein is present in the majority of patients with the disease. However, investigators are still in the early stages of identifying and developing compounds capable of targeting mutations that activate the pathway, said Lukas E. Dow, PhD.

“The goal is to understand what we can do to [increase responses to] immunotherapy. One potential option is targeting the Wnt pathway,” said Dow. “Good preclinical evidence [in liver cancer and melanoma] suggest that suppressing Wnt in tumor cells allows T cells and other components of the immune system to target tumor cells more effectively.”

In an interview during the 2019  OncLive  State of the Science Summi on  Gastrointestinal Cancers, Dow, an assistant professor of biochemistry and medicine at Weill Cornell Medicine, highlighted ongoing research evaluating Wnt as a potential target in CRC.

OncLive: Could you discuss the potential applications of targeting the Wnt pathway in CRC?

Dow: The Wnt pathway is activated or mutated in more than 95% of CRC cases. I discussed potential ways to target it. At the moment, there is no clinical compound that has received FDA approval. We're operating on preclinical models to understand where [Wnt-targeted therapies] would be effective and what we can do to make it more effective. 

Is there potential for Wnt-targeted therapies to be used as frontline or second-line treatment in the future?

I believe they will be used in treatment. At the moment, we have phase I trials for Wnt-targeted therapies. There is good reason to believe that these agents will be effective. It's unlikely they'll end up being used in isolation, but rather in combination. We are doing a lot of work in the preclinical space to try and define those combinations so that we can streamline clinical trials.

Could you expand on some of the combinations that are being evaluated?

There is a phase I trial that's no longer recruiting and is evaluating a porcupine inhibitor, which blocks Wnt ligand release from cells. The inhibitor was tested in CRC that have R-spondin fusions because they rely on the Wnt ligand, as do BRAF mutations. Therefore, they were combined with BRAF inhibitors as well as an EGFR inhibitor to try to block MAPK activation. There are two other trials that are actively recruiting and are examining similar porcupine inhibitors. However, these are early-phase, dose-escalation trials that are being conducted to look at safety. Once safety is established, it is likely that these compounds will be combined with existing therapies that we know target relevant pathways.

Could you highlight the impact of immunotherapy in this space?

In general, immunotherapy is great. However, its use in CRC is pretty limited. There are FDA-approved immunotherapies for patients with microsatellite instability—high or hypermutated CRC. In general, these therapies show relatively good responses. However, for the 95% of patients with microsatellite stable disease, immunotherapy has a very poor response rate.

What is the key takeaway from this work?

We have reason to be hopeful about strategies targeting the Wnt pathway, but we need to pay close attention to the types of mutations that activate this pathway as well as other cancer-associated mutations that occur in those cells, as they could impact the way the cell responds to Wnt suppression.

What does the future of Wnt research look like?

[Our research] is being guided by the clinic. We are trying to learn from the types of alterations that we see in the clinic through genomic profiling and from early-phase clinical trials to understand what is working and what is not. Then, we can address clinically relevant questions. We are focused on trying to define what, from a genetic standpoint, would be most susceptible to Wnt therapies as well as those who may show complete resistance to targeted approaches, so that we can define a patient subset that is the most likely to respond to these compounds in the clinic.