Queen’s University researchers have gained recognition for the discoveries they have made in medicine, engineering and the sciences; innovations that have improved the lives of people around the world. To make sure that the university and the public can continue to benefit from this work, Queen’s Partnerships and Innovation (QPI) promotes the discoveries of university researchers for the purposes of commercialization and whose work is ready for licensing and commercial application. QPI leads the commercialization processes, including the protection of the intellectual property, the creation of strategies to further its development, the search for funders, partners and licensees, the negotiation of terms, the management of relationships, and the collection of licensing and royalty revenues and their disbursement to inventors.
Here’s a grim fact. Ninety percent of all cancer fatalities result from metastasis – the rampant spread of cancer throughout the body. Underlying this frightening phenomenon is an unbridled actin cytoskeleton, a dynamic network of actin polymers and associated binding proteins that fill the cell’s interior and provide protrusive and contraction forces that power migration of cancer cells from one location in the body to another. If there were a way to disrupt actin networks in cancer cells specifically, perhaps metastasis could be prevented.
That’s the idea that three Queen’s researchers are working on. It’s a complex endeavor, one that has called on the very divergent skills of its lead researchers, Professors John Allingham (Biomedical Molecular Sciences), P. Andrew Evans (Chemistry) and Andrew Craig (Queen’s Cancer Research Institute). But the payoff, if they succeed, will be an incredible benefit to literally thousands of people who might otherwise face death at the hands of metastatic cancers.
Their story begins in 2003, when Dr. Allingham was a postdoctoral fellow in Dr. Ivan Rayment’s lab at the University of Wisconsin in Madison with an interest in the structure-function relationships of cytoskeleton proteins. He and his colleagues were feverishly trying to obtain complexes of actin polymer fragments bound to myosin motors (a family of proteins that play a part in muscle contraction), and he became intrigued with a class of toxic marine natural products that could break and cap actin polymers with high potency, thereby creating the actin polymer fragments they needed.
“Our research gained attention from a handful of marine natural products chemists, as far away as Japan and New Zealand, who had isolated some extraordinarily elaborate-looking cytotoxic compounds that they suspected would bind and break actin polymers. They were right!” Closer investigation revealed that nearly all these marine compounds bound to the exact same site on actin. “We recognized right away that if we could make a simplified form of these, we could find a way to target them to cancer cells.”
In other words, disrupting the actin cytoskeleton in cancer could lead to treatments for metastatic cancers.
The key was to simplify while retaining function. The naturally occurring compound was, says Dr. Evans, “just too complicated” to recreate, but simpler analogs that retained the core actin-binding component shared by all the natural compounds should be sufficient to carry out their actin-inhibiting work. Evans, a synthetic organic chemist, was introduced to Allingham in the hopes he could help the latter by creating a simpler version of the natural compound. To date, Dr. Evans has produced thirty or more compounds. Together with Dr. Craig, who was already interested in finding ways to curb metastasis through inhibition of actin-dependent processes, they applied for funding from the Collaborative Health Research Projects (CHRP) program in 2014-15.
With the $497,500 they received from CHRP, they set out to design, synthesize, and attain proof that miniature derivatives of Mycalolide B, a macrolide found in marine sponges, could mimic the actin cytoskeleton-disrupting effects of the natural form, and potently suppress the proliferation, migration and invasion of breast and ovarian cancer cells. Their results were documented in a paper published in the journal JACS in 2021.
“Based on our progress around that time,” says Dr. Craig, “we were able to get additional funding from the New Frontiers program,” a federal program created specifically to support inter-disciplinary projects such as theirs.
Over the last five years, as their work has progressed, the three researchers have been working with Michael Wells and Angela Lyon at Queen’s Partnerships and Innovations (QPI). QPI has helped them to prepare and submit a successful patent application for the United States.
What they have is promising.
“There have been other compounds developed to target actin cytoskeleton,” Wells says. “But one of the key things in pharmaceuticals is composition of matter – chemicals that have never been made before.”
While it’s hard to commercialize an idea based on a method or a use, he says, pharmaceutical companies pay attention if the chemical composition is novel. The team has continued to develop new compounds, which, he says, “could be a completely different [patent] application.”
In the meanwhile, the team continues working on a number of challenges. A key one is targeting their actin inhibitors to cancer cells and not healthy cells.
“We’re looking at a number of different approaches,” says Allingham. “One approach that we are putting a lot of energy into is using an antibody that seeks out a specific receptor that’s abundant on certain types of cancer cells.”
The challenge here, he says, involves attaching their compound to the antibody. One possibility is to use a glycan polymer, which is appealing because it “enables strict control over the site and number of compounds added to the antibody.”
To that end, they have begun working with Professor Chantelle Capicciotti at Queen’s, an expert in glycan engineering. If they can make sure it targets only cancerous cells, says Evans, “I think you’ll see a lot of people jump on board.”
One possibility, he says, would be to work with a group they have connections with at MIT who could spin it out, or they could do something on their own. “Something like this could be quite valuable to a pharma or a biotech company.”
Readers interested in licensing or learning more, about the technology Drs. Allingham, Craig and Evans have developed, should visit Queen's technology information page and contact Michael Wells at michael.wells@queensu.ca.