UIC drug crosses blood-brain barrier, now in clinical trials for cancer patients
A drug invented at the University of Illinois at Chicago is now being studied in humans as a treatment for difficult-to-treat and chemoresistant cancers including glioblastoma, or GBM, the deadliest type of brain tumor.
UIC professor Irina Gaisina, one of the inventors of the drug, has been closely involved in its research and development, which began more than 10 years ago.
“We were developing a series of potent therapeutics for bipolar disorder when I came across an article on promising cancer interventions,” said Gaisina, assistant professor of medicinal chemistry and pharmacognosy in the UIC College of Pharmacy. “The article suggested the same target we were researching for bipolar disorder was being studied elsewhere for cancer.”
The UIC series of inhibitors, which were based off a natural product, staurosporine, worked on an enzyme found in cells called glycogen synthase kinase-3beta, or GSK-3beta, which regulates diverse cell-signaling pathways. In bipolar disorder, increased activity of GSK-3beta is linked to behavioral changes and neural degeneration. In cancer, overexpression of GSK-3beta helps tumor cells survive and resist chemotherapy treatment.
“We contacted the authors of the article, who were at the Mayo Clinic, and began collaborating to test our compounds in their cancer assays,” Gaisina said.
Starting with cell models of pancreatic cancer, Gaisina and her collaborators administered the best of their GSK-3beta inhibitors to the tumor cells. The initial results were unexpected — they found no correlation between the potency of the inhibitor and its ability to stop cancer cell growth.
“While we were surprised to discover our most powerful in vitro GSK-3beta inhibitors were not the best performers in cancer cell cultures, these findings shed light on a very important discovery,” Gaisina said, “that there needs to be certain structural elements in the drug molecule to prevent the cancer cells from detecting the inhibitor and rejecting it from the cell.
“The challenge was to create something that could withstand the metabolic processes of both the cancer cell and the human body,” Gaisina said. “So we set out to test the relationship between the inhibitors’ molecular structures and their biological activity.”
Through a series of structure-activity relationship studies and a few rounds of structural optimization called “tailoring,” the UIC team developed 9-ING-41, a highly potent and selective GSK-3beta inhibitor that, unlike its predecessors, is metabolically stable and maintains effective concentration in tumors. When tested in animals, which was done in close collaboration with researchers at Northwestern University, treatment with the drug led to significant tumor regression and increased overall survival.
“The biggest challenges in cancer treatment are drug toxicity and chemoresistance,” Gaisina said. “9-ING-41 is a targeted therapeutic with low general toxicity, and early tests have shown it to be very effective when used alone or in combination with conventional chemotherapy to both enhance the effect of chemo and prevent chemoresistance.”
Due to its history of development as a potential treatment for bipolar disorder, the drug is non-toxic to neurons and lipophilic, which enables it to penetrate the blood-brain barrier. Gaisina says this makes it a particularly promising treatment for glioblastoma and other brain tumors, especially when combined with its low general toxicity and selective nature.
UIC licensed the patents and intellectual property for 9-ING-41 to Actuate Therapeutics, Inc., a clinical-stage pharmaceutical company, in 2015. Following approval of 9-ING-41 as an investigational new drug by the U.S. Food and Drug Administration in February, Actuate announced this week the opening of a phase I/phase II clinical trial.
“The development of 9-ING-41 is a testament to UIC’s ability to collaborate not only across our campus but with other U.S. and international institutions, as we did with the Mayo Clinic and Northwestern University to develop this drug,” Gaisina said.
9-ING-41 is one of many UIC drug candidates being developed by licensees through the university’s Office of Technology Management, joining two others currently being investigated in humans as treatments for cancer.