Updated: May 29, 2022 11:44 p.m. STI
Washington [US]May 29 (ANI): A small molecule has been identified that blocks a key pathway in brain tumors, according to scientists at the University of Michigan Rogel Cancer Center.
However, there was a problem with how to get the inhibitor through the bloodstream and into the brain to reach the tumor. Working with several labs, the teams fabricated a nanoparticle to contain the inhibitor, and the results were even better than expected.
Not only did the nanoparticles deliver the inhibitor to the tumor in mouse models, where the drug successfully activated the immune system to eliminate the cancer, but the process triggered immune memory such that a reintroduced tumor also been eliminated – a sign that this potential new approach could not only treat brain tumors, but also prevent or delay recurrences.
“Nobody could get this molecule into the brain. It’s really a milestone. Outcomes for glioma patients haven’t improved in the last 30 years,” said Maria G. Castro, PhD, RC Schneider Collegiate Professor of Neurosurgery at Michigan Medicine. Castro is the lead author of the study, published in ACS Nano.
“Despite survival gains in many cancer types, glioma remains stubbornly difficult, with only 5% of patients living five years after their diagnosis,” said study author Pedro R. Lowenstein, MD, PhD. , Richard C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine.
Gliomas are often resistant to traditional therapies, and the environment inside the tumor suppresses the immune system, rendering newer immune therapies ineffective. Add to that the challenge of crossing the blood-brain barrier, and it becomes even more difficult to deliver effective treatments to these tumors.
The Castro-Lowenstein laboratory saw an opportunity. The small molecule inhibitor AMD3100 was developed to block the action of CXCR12, a cytokine released by glioma cells that forms a shield around the immune system, preventing it from firing against the invading tumor. The researchers showed in mouse models of glioma that AMD3100 prevented CXCR12 from binding to immunosuppressive myeloid cells. By disarming these cells, the immune system remains intact and can attack the tumor cells.
But AMD3100 struggled to reach the tumor. The drug didn’t travel well through the bloodstream and it didn’t cross the blood-brain barrier, a key problem for getting drugs into the brain.
The Castro-Lowenstein lab collaborated with Joerg Lahann, PhD, Wolfgang Pauli Collegiate Professor of Chemical Engineering at UM College of Engineering, to create protein-based nanoparticles to encapsulate the inhibitor, hoping to help it cross blood flow.
Castro also reached out to Anuska V. Andjelkovic, MD, Ph.D., professor of pathology and research professor of neurosurgery at Michigan Medicine, whose research focuses on the blood-brain barrier. They noted that glioma tumors create abnormal blood vessels, interfering with normal blood flow.
The researchers injected nanoparticles loaded with AMD3100 into mice with gliomas. The nanoparticles contained a peptide on the surface that binds to a protein found primarily on brain tumor cells. As the nanoparticles traveled through the bloodstream to the tumor, they released AMD3100, which restored blood vessel integrity. The nanoparticles could then reach their target, where they release the drug, thereby blocking the entry of immunosuppressive myeloid cells into the tumor mass. This allowed immune cells to kill the tumor and delay its progression.
“If you don’t have blood flow, nothing will reach your target. That’s why tumors are so smart. But AMD3100 restores conduits, which allows nanoparticles to reach the tumor,” Castro said.
Other studies in mice and patient cell lines demonstrated that coupling the AMD3100 nanoparticle with radiation therapy enhanced effect beyond the nanoparticle or radiation alone.
Among the mice whose tumors were removed, the researchers then reintroduced the tumor, simulating a recurrence. Without any additional therapy, 60% of the mice remained cancer free. This suggests that, like a vaccine, AMD3100 created immune memory, allowing the immune system to recognize and destroy reintroduced cells. Although it prevented a recurrence in mice, Castro said it bodes well for at least delaying recurrence in humans.
“Every glioma reproduces. It’s very important for glioma therapy to have this immunological memory,” Castro said. Initial tests showed little to no impact on liver, kidney or heart function and normal blood counts in mice after treatment. The nanoparticle has a similar base to those that have already been tested in humans and found to be safe. Additional safety testing is needed before proceeding to a clinical trial. (ANI)