Donnelly Researchers Rapidly Identify New Drug Target and Develop Antibodies to Kill Pancreatic Cancer Cells

Researchers at the University of Toronto have developed a process that dramatically cuts the amount of time it takes to create new cancer treatments. Using a breakthrough technology, their study, published this week in Nature Medicine, identified a new potential drug target in a class of pancreatic cancer, and unveiled a new treatment option that exploits genetic faults to destroy cancer cells.

Professors Jason Moffat and Sachdev Sidhu from the Donnelly Centre and the department of molecular genetics, along with Professor Stephane Angers from the Leslie Dan Faculty of Pharmacy, made this discovery using the cutting-edge CRISPR-Cas9 genome editing technology.

Using this revolutionary tool, the teams probed the function of every single gene expressed by pancreatic cancer cells to determine that one of the receptors (Frizzled-5) is essential for the growth of mutant pancreatic cancer cells. Normally, the signaling pathways activated by Frizzled-5 tell cells when to divide, what types of cells to become, and when they should die. When mutated or deregulated, however, they can initiate tumour growth.

"This is the first time that we are able to identify bona fine genetic weaknesses in cancer cells that we can target with drugs, which will not harm healthy tissue," said Moffat.

Having identified the key role that the Frizzled-5 receptor plays in promoting pancreatic cancer growth, the team rapidly developed an antibody drug to inhibit the growth of these cells. The study showed that the antibody proved highly effective in killing the cancer cells in patient-derived samples and shrank tumours in mice without damaging the surrounding healthy cells.

Leveraging the Donnelly Centre’s state-of-the-art platform for custom antibody design, the team was able to create a targeted antibody in months – a fraction of the time it would normally take to develop a safe and effective treatment for a specific cancer.

"Our technology allows us to quickly develop a drug that's tailored to a particular kind of cancer and ready to be tested on people. In this study we show that the approach works for a type of pancreatic cancer, but this is only the tip of the iceberg," said Sidhu.

As part of this study, the team also explored the role of this receptor in colorectal cancer, a form of cancer that shares common features with pancreatic cancer. The results of this study indicate that Frizzled-5 may be a factor across multiple cancer types, broadening the potential use of anti-Frizzled-5 antibodies as a targeted cancer therapy.

“Ultimately, this study revealed genetic vulnerabilities in pancreatic cancer cells that could be exploited through the development of new targeted antibodies to inhibit tumor growth,” said Angers. “By targeting the exact signaling circuit activated in these tumors, these rapidly developed antibodies have shown considerable promise as a cancer treatment. Moreover, the state-of-the-art antibody development platform developed at U of T is a transformational leap forward in our ability to rapidly create exciting new treatments to combat various cancers.”