More than one use?
Another promising aspect of the work is that this therapy might work in other storm scenarios.
“The [cytokine storm] phenomenon we studied is not specific to COVID,” Gujral said. “It’s how immune cells respond to a threat. It could be a viral assault, or bacterial, or cancer. What we’re studying is a response of the immune cell. It doesn’t matter where the threat comes from.”
Chan, lead author on the paper, said the versatility of the platform is also significant.
“We now have the ability to define a very specific assay that can measure the phenotype you want,” she said. “The phenotype is the problem you’re trying to solve for, in this case, it’s the cytokine release from immune cells. Then you couple that with this machine learning platform to screen for FDA-approved drugs that will block the phenotype you’re trying to measure. I think that’s very powerful.”
Gujral, Chan and team put the drug’s cytokine storm-dampening effect to the test with a mouse that developed sepsis, another type of storm, following a lung infection.
“It cleared the infection,” Gujral said.
But the researchers cautioned that “there’s a fine balance” between suppressing a cytokine storm and suppressing necessary immune function.
“You want the immune system to fight the virus or whatever the threat is,” Gujral said. “You want to show that you’re not suppressing it indefinitely, that you’re not suppressing all the immune cells.”
To that end, in collaboration with Hutch virology experts McNevin and McElrath, who holds the Joel D. Meyers Endowed Chair, the team tested how ponatinib worked against cytokine release by two different types of immune cells: monocytes and T cells.
“We found the drugs affected the ability of the monocytes to secrete cytokines,” Gujral said. “But they had little effect on T cells.”
Bender Ignacio said it was important to inhibit the hyperinflammatory response triggered by a subset of immune cells while theoretically allowing preservation of the parts of the immune system needed to fight the virus. The steroids currently being used to suppress the immune response are a “blunt tool,” she said.
“Looking at these precision tools is very important and may allow them to be used earlier in some cases,” she said. “There’s also potential for using them in people who never develop severe disease, to either prevent or treat long COVID.”
Applying it to cancer
The Hutch team is thrilled by the success; Gujral called it a “a nice validation of the drug-discovery approach.”
Chan added that coming up with fast answers mid-pandemic felt incredibly rewarding.
“Whether this can have a translational impact depends on many stakeholders,” she said. “But this is an unprecedented time. As a scientist, I’m very excited that we can apply our platform to this crisis and find a solution. It feels very rewarding and also shows how versatile and flexible research can be.”
Best of all, it’s just the start.
The team’s latest proof-of-concept paper in the Proceedings of the National Academy of Sciences shows the approach’s promise for late-stage prostate cancer.
“One of the challenges of prostate cancer is when it metastasizes to different organs,” Gujral said. “It’s very painful and very difficult to treat.”
He, Nelson and their team used the same polypharmacology-based approach to identify the kinase inhibitors that curtail prostate cancer cell growth. Their goal was to find inhibitors that block several kinases involved in prostate cancer growth and progression but aren’t likely to cause widespread side effects.
Two compounds, PP121 and SC-1, met these criteria and suppressed prostate tumor growth in lab dishes and in preclinical models in which human tumors are allowed to grow in mice.
The team hoped that the new compounds could also work against tumor spread, including tumors that spread to the bone.
“Bone metastases are very painful for patients, and very hard to treat because of the complexity of the bone microenvironment,” Gujral said.
He and Nelson teamed up with Dr. Eleonora Dondossola at the University of Texas MD Anderson Cancer Center to test their compounds’ potential against bone metastases. Dondossola had developed a new approach to model the molecular and cellular environment that tumor cells encounter in bone by studying both a lab dish-based system of scientist-engineered bone tissue and tumor cells implanted into bone.
“The most innovative aspect of our work lies in the ability to predict the activity of a therapeutic agent to influence a certain parameter (in our case tumor growth) through a computational system,” Dondossola said, noting that the computational approach saved the team time and resources when identifying and testing PP121 and SC-1.
The initial tests of the compounds against tumor cells growing in Dondossola’s engineered bone tissue looked promising. But when she and Gujral first tested their compounds against prostate tumor cells implanted into and allowed to grow in bone, the results were disappointing: Tumors grew at a normal rate.
But when they tested their kinase inhibitors combined with docetaxel, a standard chemotherapy for metastatic prostate cancer, they found that the drug combo slowed bone metastasis growth by six times compared to docetaxel alone. The combination also prolonged mouse survival, from less than 50 days to 120 days.
Dondossola and Gujral are now working to understand how PP121 and SC-1 may help make bone metastases more sensitive to docetaxel.
“If we can understand that part of the biology better, we could probably come up with even better [drug] combinations,” Gujral said.
PP121 and SC-1 have yet to be approved by the FDA for use as therapeutics, but Gujral hopes that will change soon. The Hutch and MD Anderson recently filed a patent application for the use of these compounds with docetaxel as a treatment against metastatic prostate cancer. More preclinical testing is in the works.
“This really opens up a new area for biologists to look at the role of kinases in various diseases,” he said.
This work was funded by the Fred Hutch COVID-19 Pilot Fund, the National Cancer Institute, the Pacific Northwest Prostate Cancer and MD Anderson Cancer Center SPOREs, the Department of Defense and an AACR-Bayer Innovation and Discovery Grant.
Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.