Drugs that block the checkpoint PD-1 to unleash an immune attack against cancer are effective in several tumor types, but figuring out why some patients don’t respond has been a challenge. Now two separate teams have published research that could improve efforts to use immuno-oncology drugs in two of the hardest cancers to treat—lung cancer and glioblastoma.
In the first study, researchers in China zeroed in on two cell-signaling pathways in glioblastoma that increase the production of PD-L1, a checkpoint protein that binds to PD-1 and cripples the immune system’s T cells. They discovered they could inhibit this process in mouse models of glioblastoma by combining an experimental compound from Merck, MK-2206, with an anti-PD-1 antibody. They published the study in the Journal of Experimental Medicine.
MK-2206 inhibits protein kinase B (AKT), which has long been a popular target in oncology research because of research showing that it promotes cancer cell survival and resistance to chemotherapy. Several trials of the drug were completed, and one that’s not sponsored by the company is ongoing in breast cancer. But a study published in 2019 concluded that MK-2206 had little clinical effect in breast cancer.
Still, MK-2206 was of interest to the China research team because of its potential to be used in combination with PD-1 inhibitors. Their research showed that some glioblastoma patients have mutations that activate two pathways called Wnt and EGF signaling, which in turn activates the gene that makes PD-L1.
In the mouse models, MK-2206 alone boosted the number of T cells traveling to glioblastoma tumors, slowing tumor growth and prolonging survival, they reported. "Combining MK2206 with an anti-PD-1 antibody further enhanced T cell infiltration and was even more effective at blocking tumor growth," said co-senior author Jianxin Lyu, a professor at Wenzhou Medical University in China, in a statement.
In the second study, a Spanish research team identified a non-coding RNA that helps lung cancer cells escape immune detection. Non-coding RNAs are produced in a part of the genome that’s often referred to as “junk DNA,” because it doesn’t make proteins. So the role of these non-coding RNA molecules has been somewhat of a mystery.
Researchers at the University of Navarra in Pamplona studied 7,000 tumor samples and discovered that some lung cancer cells have extra copies of a gene that makes a non-coding RNA, which they dubbed amplified lncRNA associated with lung cancer-1 (ALAL-1). When they tamped down ALAL-1 in mice, tumor growth slowed, they reported in the Journal of Cell Biology.
ALAL-1 works by shuttling the enzyme USP4 into the cell nucleus, which influences the activity of more than 1,000 genes, the researchers discovered. That reduces signals that would normally attract cancer-killing immune cells, they said.
Inhibiting ALAL-1, therefore, “could have a 'double-hit' anti-tumor effect: on the one hand, by decreasing the autonomous capacity of cancer cells to survive and proliferate, and on the other hand, by promoting the ability of immune cells to infiltrate and attack the tumor," said co-author Maite Huarte of the University of Navarra in Pamplona, in a statement.
Huarte added that combining checkpoint inhibitors with drugs that block ALAL-1 could be a promising approach for treating lung cancer patients who fail to respond to immune-boosting drugs.