Southern Research scientists are targeting a mechanism used by tumor cells to disarm the human immune system as they work to develop a new drug that’s effective against multiple forms of cancer and easy to administer as a pill.
The Southern Research team is building on a successful strategy in immunotherapy – prevent a protein from the tumor from interacting with a protein from the immune system’s T-cells in a way that shuts down an attack on the cancer.
This interaction, called the PD-1/PDL-1 checkpoint, is the foundation of FDA-approved cancer medicines and the subject of intense research in the exploding field of immune-oncology, which unleashes the body’s immune system to fight cancer cells.
“Ideally, the T-cells will attack and kill cancer cells,” said Dr. Bo Xu, M.D., Ph.D., Distinguished Fellow and Chair of Southern Research’s Oncology Department. “But the tumor cells making the PD-L1 protein fool the T-cells to turn on the PD-1 pathway.
“The tumor-infiltrating T-cell isn’t able to function properly and will undergo cell death mechanism,” he added. “That’s how a tumor invasion becomes effective.”
Cancer treatments that block this protein-protein interaction have shown remarkable effectiveness. But the antibody-based therapies now on the market require patients to receive massive infusions. These drugs are also very expensive, costing $150,000 a year or more.
Southern Research is taking a different approach as part of this drug discovery project, according to Rebecca Boohaker, Ph.D., a research assistant fellow in the Oncology Department.
“There are lots of reasons to move away from antibodies. The chief reason is that antibodies are long-lived in your system; they’re hard to clear out,” Boohaker said. “That’s why there are a lot of side effects to antibody therapy, such as auto-immune issues from having your immune system perpetually on.”
Southern Research, which has discovered seven FDA-approved drugs used in cancer treatment, is working to develop a small molecule PD-1/PDL-1 checkpoint inhibitor that can be delivered in pill form.
“If we can provide a bio-available oral drug that works on this known, well-established target, we will lower the cost for the treatment,” Xu said.
The Southern Research team has set out to design a targeted small-molecule peptic mimic, or protein-like fragment, that acts as a blockade to prevent the fateful encounter between the T-cell’s PD-1 and the tumor’s defensive PDL-1 protein. Block that interaction, and the immune system can go about its business of eliminating cancer cells.
“We’re finding that this immune checkpoint is almost built into the way that the tumor is going to respond to any sort of attack,” Boohaker said.
Already, tens of thousands of drug-like compounds have been tested at Southern Research’s state-of-the-art High Throughput Screening Center, and promising lead compounds have been identified for optimization.
Boohaker said the fact that the targeted PD-1 protein is found on the surface of the T-cell is an advantage for the research team.
“We don’t have to worry about our compound getting into the cell. That gives us a head start. All we have to do is to block just a portion of these interacting proteins,” she said.
HOPE FOR A CURE
Xu said the rapid development of checkpoint inhibitors in recent years has fueled hopes that cancer can be potentially cured. Plus, therapeutics that block this protein-protein interaction and re-activate the human immune system could be useful to treat many forms of cancer.
“The immune system operates in a predictable way, so it’s more like hitting a fixed target than a cancer that could have any number of mutations that cause problems. That’s a moving target,” Boohaker said.
“As you kill off the first round of tumor cells, you have recurrence, and that’s a whole different set of problems that may not be responsive to that therapy,” she added. “This has the potential to be a long-term fix.”
Though the team is encouraged by the project’s progress, the scientists know it could be years before their research pays off in the form of a new immunotherapy drug.
“We’re not targeting the cancer directly. We’re trying to target the immune system, and that calls for intricate experimental designs, with multi-layered analyses,” Boohaker said.
“It’s not as simple as ‘Does it kill the cancer?’ We want to make sure it’s doing it the right way and working on the right pathways, and that it is doing exactly what we set out to do when we targeted that protein.”
The Alabama Cancer Research Consortium and Southern Research are funding the project.