This is an excerpt of an article in Duke-NUS Medicus 2021 issue 4.
The (Wnt)ing way: Fighting cancer with ETC-159
Wnts, which instruct cells on what they should become, are only found in multicellular animals, but not in single cell organisms such as yeast or amoebas, which don’t have as much need for proteins that communicate with neighbouring cells.
“Wnts have been evolving for 500 million years,” said David Virshup, Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS.
“So, they came about really early in development to probably signal between one cell and the next to tell them, ‘I’m left and you’re right; I’m up and you’re down’, ‘I’m going to turn into a kidney cell, so you should turn into a nerve cell’,” added Virshup to illustrate how Wnts mediate cell-to-cell communication.
In humans, cellular communication becomes much more complex, requiring 19 different Wnt genes to run smoothly, with some of the Wnts even implicated in other important cellular processes such as inflammation and immunity.
But Wnts also have an altogether more sinister side because when they go rogue and are overexpressed, they can drive the formation of cancerous growths.
“Then, it turns out that there are other ways to activate the Wnt pathway in cancer, not just overexpressing the Wnt, but for instance, mutation to parts of it,” said Virshup.
“One of the things they do in certain tissues is they tell cells whether to remain stem cells or stop being stem cells,” he added.
In cancers that are addicted to Wnt signalling, the Wnt pathway remains highly activated, allowing cancerous cells to proliferate like stem cells, thereby feeding the cancer.
Going against the flow
The next logical step, then, was to determine if Wnt signalling could be inhibited to stop the growth of these Wnt-addicted cancers.
“When I first had this idea back in Utah, there was a fair amount of skepticism that this was a good idea,” said Virshup. “Because the general idea was that Wnt signalling was so important, if you inhibit it with a broad-spectrum inhibitor, you’ll just kill people.”
But Virshup persisted and got his student at the time, Zahra Kabiri, to study how knocking out Wnt signalling would affect adult mice.
They expected the worst, but somehow, the mice survived—living proof that it was indeed possible to inhibit Wnt signalling in adults.
“Since I’m a physician, it’s always in the back of my mind—what’s druggable and where could we make a difference in understanding that might lead to drugs,” said Virshup.
Embarking on the ETC-159 journey
This vision became a reality after he arrived in Singapore in 2007 to set up his current laboratory.
Virshup reached out to Dr Alex Matter, who was then heading the Experimental Therapeutic Centre (ETC) at the Agency for Science, Technology and Research (A*STAR). At that time, Matter was in the process of scouting for new drug targets that could be validated.
“David came with a validated target,” he said, “and it’s very difficult to find drug targets that are validated, with the biology and clinical sides really matching and the target causally related to the disease.”
“With David, I knew I was dealing with a very serious, very experienced scientist whom I could trust,” added Matter.
Even with a validated target in hand, chemists and biologists at ETC had to test some 200,000 compounds in order to find some useful lead structures.
“Once we had some lead structures, we had to optimise each lead until they were fit to progress ultimately into preclinical development,” said Matter.
In 2013, ETC handed over a fully optimised lead, ETC-159, as a development candidate to D3 (Drug Discovery & Development), which later merged with ETC and the Experimental Biotherapeutics Centre to form the Experimental Drug Development Centre (EDDC).
“After that, there were extensive preclinical studies to make sure that we understood its potential toxicity before moving on to humans,” said Virshup.
“We would not have been able to make a molecule on our own. Their help was invaluable. The partnership was invaluable,” he added.
The road ahead
As ETC-159 progresses through clinical trials managed by EDDC, Dr Veronica Diermayr continues the scientific collaboration with Virshup’s laboratory.
“It’s a stimulating symbiosis,” said Diermayr, the asset development leader for this project, describing the process of collaborating with Virshup, before adding, “They (Virshup’s team) stimulate you with new ideas; they bring up targets that we wouldn't have taken on without his strong support at that time.”
Diermayr’s team led the drug into Phase 1 clinical trials, with the first patient dosed in January 2015. As the clinical trial progressed, additional test sites in the United States were added, bringing the total number of patients treated by the end of Phase 1A to 32.
For the drug to progress through clinical trials, the team decided to select a patient population in whom ETC-159 would be an effective cancer treatment by using suitable biomarkers. So, Diermayr and her team worked to establish the most robust biomarker for clinical use from a list of potential biomarkers provided by Virshup.
“When you want to see efficacy, you can do this best if you have the right kind of patients for whom this drug has a high likelihood to work,” she explained.
That data also gave the team a deeper understanding of how the drug works, leading to further studies on the effect of ETC-159 in different patient populations as the clinical trial progressed to Phase 1B, which kickstarted in July 2020.
In the Phase 1B trial, the team is studying whether ETC-159 is effective as a single agent in genetically defined subgroups of colorectal, endometrial or ovarian cancer patients with limited treatment options. The study will also determine the effectiveness of combining ETC-159 with immune checkpoint inhibitors in subsets of the same cancers that are currently unresponsive to checkpoint inhibitors.
“It would be ground-breaking if the team was able to achieve clinical proof-of-concept, demonstrating that tumours known to be unresponsive to checkpoint inhibitors could become responsive with the addition of ETC-159,” said EDDC’s Chief Executive Officer, Professor Damian O’Connell.
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